Compounds, compositions and methods of using same for modulating uric acid levels

ABSTRACT

Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of making and using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.61/094,388, filed Sep. 4, 2008, and U.S. Provisional Application No.61/180,110, filed May 20, 2009, both of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

Aberrant uric acid levels are related to several disorders including,but not limited to, gout, gouty arthritis, inflammatory arthritis,kidney disease, nephrolithiasis (kidney stones), joint inflammation,deposition of urate crystals in joints, urolithiasis (formation ofcalculus in the urinary tract), deposition of urate crystals in renalparenchyma, Lesch-Nyhan syndrome, and Kelley-Seegmiller syndrome.

SUMMARY OF THE INVENTION

Disclosed herein, in certain embodiments, is a compound of formula (I):

wherein:

-   -   X is O or S;    -   L is —(CR^(x)R^(x′))_(x)—(CR^(y)R^(y′))_(y)—(CR^(z)R^(z′))_(z)—;        wherein x is 0 or 1; y is 0 or 1; z is 0 or 1; R^(x), R^(x′),        R^(y), R^(y′), R^(z) and R^(z′) are each independently H, F, Cl,        Br, I or optionally substituted C₁₋₃ alkyl; or R^(x) and R^(x′),        or R^(y) and R^(y′), or R^(z) and R^(z′), or R^(x) and R^(y), or        R^(y) and R^(z), or R^(x) and R^(z) together with the carbon        atoms to which they are attached, form an optionally        substituted, aromatic or non-aromatic, 3-7 membered ring,        optionally comprising 1 or 2 heteroatoms selected from O, N and        S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   R^(A) is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted n-propyl, optionally substituted        i-propyl, CF₃, CHF₂ or CH₂F;    -   R^(B) is

-   -   -   wherein a is 0, 1 or 2; R^(1a) is H or optionally            substituted C₁₋₃ alkyl; R^(1a′) is H or optionally            substituted C₁₋₃ alkyl; or R^(1a) and R^(1a′) together with            the carbon atom to which they are attached form an            optionally substituted 3-, 4-, 5- or 6-membered ring,            optionally comprising 1 or 2 heteroatoms selected from O, N            and S;        -   R^(1b), R^(1c), R^(1d), R^(1e) and R^(1f) are each            independently H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,            cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,            C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″SO₃H, S(O)₂R′,            S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″ aryl, heterocyclyl or            heteroaryl; or R^(1b) and R^(1c), or R^(1c) and R^(1d), or            R^(1d) and R^(1e), or R^(1e) and R^(1f) together with the            two carbon atoms to which they are attached, form an            optionally substituted, aromatic or non-aromatic, 5-, 6- or            7-membered ring, optionally comprising 1 or 2 heteroatoms            selected from O, N and S, and wherein said ring may be            optionally fused to 1 or 2 additional optionally            substituted, aromatic or non-aromatic, 5-, 6- or 7-membered            rings, optionally comprising 1 or 2 heteroatoms selected            from O, N and S; and wherein the optional substituents are            each independently H, F, Cl, Br, I, CF₃, CN, alkyl,            cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′,            SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,            S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl            or heteroaryl; wherein R′ is methyl, ethyl, n-propyl,            i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or            phenyl; R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl,            i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,            cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or R′            and R″ together with the nitrogen atom to which they are            attached form an optionally substituted, saturated or            unsaturated 4-, 5- or 6-membered heterocyclic ring;

    -   R^(C) is an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, OR^(2a), SR^(3a), NR^(4a)R^(4b), or a        combination thereof, wherein; R^(2a) is substituted C₁-C₄ alkyl,        optionally substituted C₅-C₁₀ alkyl, optionally substituted        heteroalkyl, optionally substituted cycloalkyl, optionally        substituted heterocycloalkyl, optionally substituted aryl or        optionally substituted heteroaryl; or R^(2a) is a        pharmaceutically acceptable cation; or R^(2a) is        —[C(R^(5a))(R^(5b))]_(m)R^(5c); R^(3a) is hydrogen, optionally        substituted C₁-C₁₀ alkyl, optionally substituted heteroalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl, optionally        substituted heteroaryl; or R^(3a) is        —[C(R^(5a))(R^(5b))]_(n)R^(5c); R^(4a) is hydrogen, optionally        substituted alkyl, optionally substituted heteroalkyl,        optionally substituted cycloalkyl or optionally substituted        heterocycloalkyl; and R^(4b) is hydrogen, optionally substituted        alkyl, optionally substituted heteroalkyl, optionally        substituted cycloalkyl or optionally substituted        heterocycloalkyl; or R^(4b) is —[C(R^(5a))(R^(5b))]_(n)R^(5c),        wherein R^(5a) and R^(5b) are each independently hydrogen,        halogen, cyano, nitro, an amino acid, a dipeptide, a tripeptide,        a tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃        alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally        substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅        alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally        substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇        cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,        optionally substituted -L-C₁-C₄ haloalkyl, optionally        substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄        alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine,        optionally substituted -L-C₅-C₇ aryl, optionally substituted        -L-C₅-C₇ heteroaryl,

R^(5c) is hydrogen, halogen, cyano, nitro, an amino acid, a dipeptide, atripeptide, a tetrapeptide, a polypeptide, a lipid, a phospholipid, aglycoside, a nucleoside, a nucleotide, an oligonucleotide, polyethyleneglycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃ alkyl, optionallysubstituted -L-C₄-C₉ alkyl, optionally substituted L-C₂-C₅ alkenyl,optionally substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl, optionallysubstituted L-C₃-C₇ cycloalkenyl, optionally substituted -L-C₃-C₇heterocycloalkyl, optionally substituted -L-C₁-C₄ haloalkyl, optionallysubstituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄alkylamine,optionally substituted -L-di(C₁-C₄)alkylamine, optionally substituted-L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂; y₁ is 0, 1, 2 or 3; Y isOH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂, OP(O)(OH)₂,OP(O)(OH)(O—-C₁₋₄ alkyl) or NY²Y³Y⁴; wherein Y² and Y³ are eachindependently hydrogen or methyl; or Y² and Y³ are taken together withthe nitrogen to which they are attached form a five or six membered ringthat optionally contains an oxygen atom or a second nitrogen atom; andY⁴ is an electron pair or an oxygen atom; m is 1, 2, 3, 4; n is 0, 1, 2,3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments, X is O. In some embodiments, X is S. In someembodiments, x is 1, y is 0 and z is 0. In some embodiments, X is S, xis 1, y is 0 and z is 0. In some embodiments, R^(x) and R^(x′) are H, For methyl. In some embodiments, R^(x) and R^(x′) are both H. In someembodiments, R^(x) and R^(x′) are both F. In some embodiments, R^(x) andR^(x′) are both methyl. In some embodiments, x is 1, y is 0, z is 0,R^(x) is H and R^(x′) is H. In some embodiments, x is 1, y is 0, z is 0,R^(x) is F and R^(x′) is F. In some embodiments, x is 1, y is 0, z is 0,R^(x) is methyl and R^(x′) is methyl. In some embodiments, X is S, x is1, y is 0, z is 0 and R^(x) and R^(x′) are either both H or both F. Insome embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) andR^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S, andwherein said ring may be optionally fused to 1 or 2 additionaloptionally substituted, aromatic or non-aromatic, 5-, 6- or 7-memberedrings, optionally comprising 1 or 2 heteroatoms selected from O, N andS. In some embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z)and R^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring. Insome embodiments, R^(x) and R^(x′) together with the carbon atoms towhich they are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring. In some embodiments, R^(x) and R^(y)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring. Insome embodiments, R^(A) is H. In some embodiments, R^(A) is Br. In someembodiments, a is 0. In some embodiments, R^(1b), R^(1c), R^(1d), R^(1e)and R^(1f) are each independently H, F, Cl, Br, I, CF₃, CN, alkyl,cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″SO₃H, S(O)₂R′, S(O)₂NH₂,S(O)₂NHR′, S(O)₂NR′R″ aryl, heterocyclyl or heteroaryl. In someembodiments, R^(1b) and R^(1c), or R^(1c) and R^(1d), or R^(1d) andR^(1e), or R^(1e) and R^(1f) together with the two carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In some embodiments, R^(1b) andR^(1c) together with the two carbon atoms to which they are attached,form an optionally substituted, aromatic or non-aromatic, 5-, 6- or7-membered ring. In some embodiments, R^(1b) and R^(1c) together withthe two carbon atoms to which they are attached, form an optionallysubstituted, aromatic 5-, 6- or 7-membered ring. In some embodiments,R^(1b) and R^(1c) together with the two carbon atoms to which they areattached, form an optionally substituted, aromatic 6-membered ring.

In some embodiments, R^(B) is

wherein R^(1g) is H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)_(s)NHR′,S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl; wherein R′ is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl orphenyl; R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl or phenyl; or R′ and R″ together with the nitrogenatom to which they are attached form an optionally substituted,saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring.

In some embodiments, R^(B) is

In some embodiments, R^(1e), R^(1f) and R^(1g) are H. In someembodiments, R^(1d) is CN, alkyl or cycloalkyl. In some embodiments,R^(1e), R^(1f) and R^(1g) are H and R^(1d) is CN, alkyl or cycloalkyl.In some embodiments, R^(1e), R^(1f) and R^(1g) are H and R^(1d) is CN or

cyclopropyl. In some embodiments, R^(B) is

In some embodiments, X is S, x is 1, y is 0, z is 0 and R^(x) and R^(x′)are either both H or both F. In some embodiments, R^(C) is an aminoacid, a dipeptide, a tripeptide. In some embodiments, R^(C) is an aminoacid or a dipeptide. In some embodiments, R^(C) is glycine, alanine orvaline. In some embodiments, R^(C) is a dipeptide comprising glycine,alanine or valine.

Disclosed herein, in certain embodiments, is a compound of Formula(I-A):

wherein:

-   -   X is O or S;    -   R^(A) is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted n-propyl, optionally substituted        i-propyl, CF₃, CHF₂ or CH₂F;    -   R^(1b), R^(1c), R^(1d), R^(1e) and R^(1f) are each independently        H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″        aryl, heterocyclyl or heteroaryl; or R^(1b) and R^(1c), or        R^(1c) and R^(1d), or R^(1d) and R^(1e), or R^(1e) and R^(1f)        together with the two carbon atoms to which they are attached,        form an optionally substituted, aromatic or non-aromatic, 5-, 6-        or 7-membered ring, optionally comprising 1 or 2 heteroatoms        selected from O, N and S, and wherein said ring may be        optionally fused to 1 or 2 additional optionally substituted,        aromatic or non-aromatic, 5-, 6- or 7-membered rings, optionally        comprising 1 or 2 heteroatoms selected from O, N and S; and        wherein the optional substituents are each independently H, F,        Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl, NH₂,        NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,        aryl, heterocyclyl or heteroaryl; wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring;    -   R^(C) is an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, OR^(2a), SR^(3a), NR^(4a)R^(4b), or a        combination thereof, wherein;    -   R^(2a) is substituted hydrogen, optionally substituted C₁-C₁₀        alkyl, optionally substituted heteroalkyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl or optionally substituted        heteroaryl; or R^(2a) is a pharmaceutically acceptable cation;        or R^(2a) is —[C(R^(5a))(R^(5b))]_(m)R^(5c);    -   R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl,        optionally substituted heteroalkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl; or R^(3a)        is —[C(R^(5a))(R^(5b))]_(n)R^(5c);    -   R^(4a) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; and    -   R^(4b) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; or R^(4b) is        —[C(R^(5a))(R^(5b))]_(n)R^(5c), wherein    -   R^(5a) and R^(5b) are each independently hydrogen, halogen,        cyano, nitro, an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃        alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally        substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅        alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally        substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇        cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,        optionally substituted -L-C₁-C₄ haloalkyl, optionally        substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄        alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine,        optionally substituted -L-C₅-C₇ aryl, optionally substituted        -L-C₅-C₇ heteroaryl,

-   -   R^(5c) is hydrogen, halogen, cyano, nitro, an amino acid, a        dipeptide, a tripeptide, a tetrapeptide, a polypeptide, a lipid,        a phospholipid, a glycoside, a nucleoside, a nucleotide, an        oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,        substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉        alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally        substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅        heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl,        optionally substituted L-C₃-C₇ cycloalkenyl, optionally        substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted        -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy,        optionally substituted -L-C₁-C₄alkylamine, optionally        substituted -L-di(C₁-C₄)alkylamine, optionally substituted        -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein

-   -   L is a bond, —C(O)—, —S(O), or —S(O)₂;    -   y₁ is 0, 1, 2 or 3;    -   Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂,        OP(O)(OH)₂, OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein Y² and        Y³ are each independently hydrogen or methyl; or Y² and Y³ are        taken together with the nitrogen to which they are attached form        a five or six membered ring that optionally contains an oxygen        atom or a second nitrogen atom; and Y⁴ is an electron pair or an        oxygen atom;    -   m is 1, 2, 3, 4;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and    -   R^(D) is a natural or unnatural amino acid residue.

Disclosed herein, in certain embodiments, is a method for inhibiting aURAT-1 transporter, comprising contacting the URAT-1 transporter with acompound disclosed herein, or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a method for decreasinguric acid levels in one or more tissues or organs of a subject in needof decreased uric acid levels, comprising administering to the subject auric acid level decreasing amount of a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof. In some embodiments, the subject in need ofdecreased uric acid levels has a disorder characterized by an abnormallyhigh content of uric acid in one or more tissues or organs of thesubject. In some embodiments, the disorder is characterized byoverproduction of uric acid, low excretion of uric acid, tumor lysis, ablood disorder or a combination thereof. In some embodiments, the blooddisorder is polycythemia or myeloid metaplasia. In some embodiments, thesubject in need of decreased uric acid levels is suffering from gout, arecurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosis. In some embodiments, thetissue or organ is blood. In some embodiments, the blood uric acid levelis decreased by at least about 1 mg/dL. In some embodiments, the blooduric acid level is decreased by at least about 2 mg/dL. In someembodiments, the uric acid levels are decreased by at least about 10% inone or more tissues or organs of the subject. In some embodiments, theuric acid levels are decreased by at least about 25% in one or moretissues or organs of the subject. In some embodiments, the uric acidlevels are decreased by at least about 50% in one or more tissues ororgans of the subject.

Disclosed herein, in certain embodiments, is a method for decreasinguric acid levels in one or more tissues or organs of a subjectcomprising administering to the subject a uric acid level decreasingamount of a compound disclosed herein or a metabolite, pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof,wherein the reduction in uric acid levels results in a reduction inhypertension or cardiovascular events.

Disclosed herein, in certain embodiments, is a method for reducing uricacid production, increasing uric acid excretion or both in a subject,comprising administering to the subject a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a method of treating asubject suffering from a condition characterized by abnormal tissue ororgan levels of uric acid comprising administering to the subject aneffective amount of a compound disclosed herein or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof. In some embodiments, the condition is characterized bylow tissue levels of uric acid. In some embodiments, the condition ischaracterized by high tissue levels of uric acid. In some embodiments,the condition is selected from gout, a recurrent gout attack, goutyarthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis. In some embodiments, the condition is gout. Insome embodiments, the condition is joint inflammation. In someembodiments, the joint inflammation is caused by deposits of uric acidcrystals in the joint. In some embodiments, the uric acid crystals aredeposited in the joint fluid (synovial fluid) or joint lining (synoviallining) In some embodiments, the method further comprises administeringan agent effective for the treatment of the condition. In someembodiments, the agent is effective in reducing tissue levels of uricacid. In some embodiments, the agent is a nonsteroidal anti-inflammatorydrugs (NSAIDs), colchicine, a corticosteroid, adrenocorticotropichormone (ACTH), probenecid, sulfinpyrazone or allopurinol. In someembodiments, the agent is allopurinol.

Disclosed herein, in certain embodiments, is a method for treating orpreventing hyperuricemia in a subject comprising administering to thesubject an effective amount of a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a method for preventing acondition characterized by abnormal tissue levels of uric acid in asubject at increased risk of developing the condition, comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof. In some embodiments, thecondition is selected from gout, a recurrent gout attack, goutyarthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis.

Disclosed herein, in certain embodiments, is a method for treating gout,a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension,a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosisin a subject comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a method for treating goutin a subject comprising administering to the subject an effective amountof a compound disclosed herein or a metabolite, pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.In some embodiments, the method further comprises administering an agenteffective for the treatment of the gout. In some embodiments, the agentis allopurinol.

Disclosed herein, in certain embodiments, is a method for preventing theformation or reducing the size of tophi/tophus in a subject, comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a method for treatinghypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in asubject comprising administering to the subject a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition comprising: a compound disclosed herein or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof; allopurinol; and optionally one or morepharmaceutically acceptable carriers.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition comprising: a compound disclosed herein or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof; at least one agent selected from the group consistingof a nonsteroidal anti-inflammatory drug (NSAID), Ibuprofen, Naproxen,Colchicine, Probenecid and Sulfinpyrazone; and optionally one or morepharmaceutically acceptable carriers.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition useful in the treatment of edema and hypertension which alsomaintains uric acid levels at pretreatment levels or causes a decreasein uric acid levels comprising: at least one antihypertensive agent; auric acid level maintaining or lowering amount of a compound of theformula (I) or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof; and optionally one ormore pharmaceutically acceptable carriers.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition useful in the treatment of cancer which also maintains uricacid levels at pretreatment levels or causes a decrease in uric acidlevels comprising: at least one anticancer agent; a uric acid levelmaintaining or lowering amount of a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof; and optionally one or more pharmaceuticallyacceptable carriers.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition useful for reducing the side effects of chemotherapy in acancer patient, comprising: a uric acid level maintaining or loweringamount of a compound disclosed herein or a metabolite, pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof;and optionally one or more pharmaceutically acceptable carriers.

This invention provides for compounds of formula (II), or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof:

wherein:

-   -   W is O, S, S(O), S(O)₂, NH, N(optionally substituted alkyl),        CH₂, CH₂O, CH₂S or CH₂NH;    -   R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH, NO₂, NH₂,        NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃,        CO₂-alkyl, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkoxy, optionally substituted        S-alkyl, optionally substituted cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl or        optionally substituted heteroaryl;    -   a is 0, 1 or 2;    -   R^(a) is H or optionally substituted C₁₋₃ alkyl;    -   R^(a′) is H or optionally substituted C₁₋₃ alkyl; or    -   R^(a) and R^(a′) together with the carbon atom to which they are        attached form an optionally substituted, 3-, 4-, 5- or        6-membered ring, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   R^(b), R^(c), R^(d), R^(e) and R^(f) are each independently H,        F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,        aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring; or    -   R^(b) and R^(c), or R^(c) and R^(d), or R^(d) and R^(e), or        R^(e) and R^(f) together with the two carbon atoms to which they        are attached, form an optionally substituted, aromatic or        non-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1        or 2 heteroatoms selected from O, N and S, and wherein said ring        may be optionally fused to 1 or 2 additional optionally        substituted, aromatic or non-aromatic, 5-, 6- or 7-membered        rings, optionally comprising 1 or 2 heteroatoms selected from O,        N and S; and wherein the optional substituents are each        independently F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,        cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′,        CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl;    -   x is 0 or 1;    -   y is 0 or 1;    -   z is 0 or 1;    -   R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each        independently H, F, Cl, Br, or optionally substituted C₁₋₃        alkyl; or    -   R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), or        R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together        with the carbon atoms to which they are attached, form an        optionally substituted, aromatic or non-aromatic, 3-7 membered        ring, optionally comprising 1 or 2 heteroatoms selected from O,        N and S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   A is H, C(O)O—B¹ or C(O)NH—B²; wherein    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation;    -   B² is H or optionally substituted C₁₋₆ alkyl; and wherein        all alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and        heteroaryl moieties may be optionally further substituted.

In some embodiments, the invention provides for compounds of formula(II).

In further or additional embodiments, the invention provides forpharmaceutically acceptable salts of compounds of formula (II). Infurther or additional embodiments, the invention provides forpharmaceutically acceptable solvates of compounds of formula (II). Infurther or additional embodiments, the invention provides forpharmaceutically acceptable polymorphs of compounds of formula (II). Infurther or additional embodiments, the invention provides forpharmaceutically acceptable esters of compounds of formula (II). Infurther or additional embodiments, the invention provides forpharmaceutically acceptable tautomers of compounds of formula (II). Infurther or additional embodiments, the invention provides forpharmaceutically acceptable prodrugs of compounds of formula (II).

In some embodiments W is CH₂, CH₂O, CH₂S or CH₂NH. In further oradditional embodiments, W is CH₂. In further or additional embodiments,W is CH₂O. In further or additional embodiments, W is CH₂S. In furtheror additional embodiments, W is CH₂NH. In other embodiments W is O, S,S(O), S(O)₂, NH, N(optionally substituted alkyl). In further oradditional embodiments, W is O, S or NH. In further or additionalembodiments, W is S, S(O), S(O)₂. In further or additional embodiments,W is O. In further or additional embodiments, W is S. In further oradditional embodiments, W is NH.

In some embodiments, R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH,NO₂, NH₂, NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃ orCO₂-alkyl. In further or additional embodiments, R¹ is H. In further oradditional embodiments, R¹ is Cl or Br. In further or additionalembodiments, R¹ is Br. In further or additional embodiments, R¹ is CH₂F,CF₂H or CF₃. In further or additional embodiments, R¹ is CN, OH or NO₂.In further or additional embodiments, R¹ is NH₂, NH(alkyl) orN(alkyl)(alkyl). In further or additional embodiments, R¹ is SO₂CH₃,SO₂NH₂ or SO₂NHCH₃. In further or additional embodiments, R¹ is COOH orCO₂-alkyl. In further or additional embodiments, R¹ is optionallysubstituted alkyl or alkenyl. In further or additional embodiments, R¹is optionally substituted alkyl. In further or additional embodiments,R¹ is optionally substituted alkoxy or optionally substituted S-alkyl.In further or additional embodiments, R¹ is optionally substitutedcycloalkyl. In further or additional embodiments, R¹ is optionallysubstituted heterocycle. In further or additional embodiments, R¹ isoptionally substituted aryl. In further or additional embodiments, R¹ isoptionally substituted phenyl. In further or additional embodiments, R¹is optionally substituted naphthyl. In further or additionalembodiments, R¹ is optionally substituted heteroaryl. In further oradditional embodiments, R¹ is substituted alkyl or alkenyl. In furtheror additional embodiments, R¹ is substituted alkyl. In further oradditional embodiments, R¹ is substituted alkoxy or substituted S-alkyl.In further or additional embodiments, R¹ is substituted cycloalkyl. Infurther or additional embodiments, R¹ is substituted heterocycle. Infurther or additional embodiments, R¹ is substituted aryl. In further oradditional embodiments, R¹ is substituted phenyl. In further oradditional embodiments, R¹ is substituted naphthyl. In further oradditional embodiments, R¹ is substituted heteroaryl. In further oradditional embodiments, R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, NH₂,optionally substituted alkyl, optionally substituted aryl or optionallysubstituted heteroaryl. In further or additional embodiments, R¹ is H,F, Cl, Br, I, CH₂F, CF₂H, CF₃, NH₂, optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl. Infurther or additional embodiments, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, CH₃, optionally substituted phenyl or optionally substitutedheteroaryl. In further or additional embodiments, R¹ is optionallysubstituted phenyl or optionally substituted heteroaryl. In further oradditional embodiments, R¹ is

In further or additional embodiments, R¹ is optionally substitutedpyridyl, optionally substituted pyrimindinyl, optionally substitutedthiazolyl, optionally substituted furanyl, optionally substitutedthiophenyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedindolyl, optionally substituted iosindolyl, optionally substitutedpyrazinyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted indazolyl, optionallysubstituted benzthiazolyl, optionally substituted purinyl, optionallysubstituted quinolinyl or optionally substituted benzisoxazolyl. Infurther or additional embodiments, R¹ is

In some embodiments, W is S and R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, optionally substituted phenyl or optionally substituted heteroaryl.In further or additional embodiments, W is O; and R¹ is H, F, Cl, Br,CH₂F, CF₂H, CF₃, NH₂, optionally substituted phenyl or optionallysubstituted heteroaryl. In further or additional embodiments, W is S;and R¹ is Br.

In some embodiments, a is 0. In further or additional embodiments, ais 1. In further or additional embodiments, a is 2. In further oradditional embodiments, a is 0 or 1. In further or additionalembodiments, a is 1, R^(a) is H and R^(a′) is H.

In further or additional embodiments, R^(a) and R^(a′) together with thecarbon atom to which they are attached form an optionally substituted,3-, 4-, 5- or 6-membered ring, optionally comprising 1 or 2 heteroatomsselected from O, N and S. In further or additional embodiments, R^(a)and R^(a′) together with the carbon atom to which they are attached forman optionally substituted 3-, 4-, 5- or 6-membered ring. In further oradditional embodiments, R^(a) and R^(a′) together with the carbon atomto which they are attached form an optionally substituted 3-memberedring. In further or additional embodiments, R^(a) and R^(a′) togetherwith the carbon atom to which they are attached form a substituted3-membered ring. In further or additional embodiments, R^(a) and R^(a′)together with the carbon atom to which they are attached form anunsubstituted 3-membered ring. In further or additional embodiments,R^(a) and R^(a′) together with the carbon atom to which they areattached form an optionally substituted 4-membered ring. In further oradditional embodiments, R^(a) and R^(a′) together with the carbon atomto which they are attached form a substituted 4-membered ring. Infurther or additional embodiments, R^(a) and R^(a′) together with thecarbon atom to which they are attached form an unsubstituted 4-memberedring. In further or additional embodiments, R^(a) and R^(a′) togetherwith the carbon atom to which they are attached form an optionallysubstituted 5-membered ring. In further or additional embodiments, R^(a)and R^(a′) together with the carbon atom to which they are attached forma substituted 5-membered ring. In further or additional embodiments,R^(a) and R^(a′) together with the carbon atom to which they areattached form an unsubstituted 5-membered ring. In further or additionalembodiments, R^(a) and R^(a′) together with the carbon atom to whichthey are attached form an optionally substituted 6-membered ring. Infurther or additional embodiments, R^(a) and R^(a′) together with thecarbon atom to which they are attached form a substituted 6-memberedring. In further or additional embodiments, R^(a) and R^(a′) togetherwith the carbon atom to which they are attached form an unsubstituted6-membered ring. In further or additional embodiments, R^(a) and R^(a′)together with the carbon atom to which they are attached form anoptionally substituted 3-, 4-, 5- or 6-membered ring, comprising 1heteroatom selected from O, N and S. In further or additionalembodiments, R^(a) and R^(a′) together with the carbon atom to whichthey are attached form an optionally substituted 3-, 4-, 5- or6-membered ring, comprising 1 oxygen atom. In further or additionalembodiments, R^(a) and R^(a′) together with the carbon atom to whichthey are attached form an optionally substituted 3-, 4-, 5- or6-membered ring, comprising 1 nitrogen atom. In further or additionalembodiments, R^(a) and R^(a′) together with the carbon atom to whichthey are attached form an optionally substituted 3-, 4-, 5- or6-membered ring, comprising 1 sulfur atom. In further or additionalembodiments, R^(a) and R^(a′) together with the carbon atom to whichthey are attached form an optionally substituted 3-, 4-, 5- or6-membered ring, comprising 2 heteroatoms selected from O, N and S.

In some embodiments, W is S, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃, NH₂,optionally substituted phenyl or optionally substituted heteroaryl and ais 0. In some embodiments, W is O, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, optionally substituted phenyl or optionally substituted heteroaryland a is 0. In further or additional embodiments, W is S, R¹ is H, F,Cl, Br, CH₂F, CF₂H, CF₃, NH₂, optionally substituted phenyl oroptionally substituted heteroaryl and a is 1. In further or additionalembodiments, W is S, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃, NH₂,optionally substituted phenyl or optionally substituted heteroaryl, a is1, R^(a) is H and R^(a′) is H.

In some embodiments, A is H. In some embodiments, A is C(O)O—B¹. Infurther or additional embodiments, A is C(O)OH. In further or additionalembodiments, A is C(O)O— optionally substituted C₁₋₆ alkyl. In furtheror additional embodiments, A is C(O)O— optionally substituted C₁₋₃alkyl. In further or additional embodiments, A is C(O)O— optionallysubstituted C₁₋₂ alkyl. In further or additional embodiments, A isC(O)O— substituted C₁₋₂ alkyl. In further or additional embodiments, Ais C(O)O—C₁₋₂ alkyl. In further or additional embodiments, A is acarboxylate anion, associated with a pharmaceutically acceptable cation.In some embodiments, A is C(O)NH—B². In further or additionalembodiments, A is C(O)NH₂. In further or additional embodiments, A isC(O)NH— optionally substituted C₁₋₆ alkyl. In further or additionalembodiments, A is C(O)NH— optionally substituted C₁₋₃ alkyl. In furtheror additional embodiments, A is C(O)NH— optionally substituted C₁₋₂alkyl. In further or additional embodiments, A is C(O)NH— substitutedC₁₋₂ alkyl. In further or additional embodiments, A is C(O)NH—C₁₋₂alkyl.

In some embodiments, x is 0. In further or additional embodiments, xis 1. In further or additional embodiments, y is 0. In further oradditional embodiments, y is 1. In further or additional embodiments, zis 0. In further or additional embodiments, z is 1. In some embodiments,x is 0, y is 0 and z is 0. In some embodiments, x is 1, y is 0 and z is0. In some embodiments, x is 1, y is 1 and z is 0. In some embodiments,x is 1, y is 1 and z is 1.

In further or additional embodiments, z is 0 and A is C(O)O—B¹. Infurther or additional embodiments, z is 0, A is C(O)O—B¹ and B¹ is H oroptionally substituted C₁₋₆ alkyl. In further or additional embodiments,y is 0, z is 0 and A is C(O)O—B¹. In further or additional embodiments,y is 0, z is 0, A is C(O)O—B¹ and B¹ is H or optionally substituted C₁₋₆alkyl. In further or additional embodiments, x is 1 and R^(x) is not H.In further or additional embodiments, A is C(O)O—B¹, x is 1 and R^(x) isnot H. In further or additional embodiments, x is 1 and R^(x) and R^(x′)are not H. In further or additional embodiments, A is C(O)O—B¹, x is 1and R^(x) and R^(x′) are not H. In further or additional embodiments, xis 1 and R^(x) is optionally substituted C₁₋₃ alkyl. In further oradditional embodiments, A is C(O)O—B¹, x is 1 and R^(x) is optionallysubstituted C₁₋₃ alkyl. In further or additional embodiments, x is 1 andR^(x) and R^(x′) are optionally substituted C₁₋₃ alkyl. In further oradditional embodiments, A is C(O)O—B¹, x is 1 and R^(x) and R^(x′) areoptionally substituted C₁₋₃ alkyl. In further or additional embodiments,x is 1 and R^(x) is methyl. In further or additional embodiments, A isC(O)O—B¹, x is 1 and R^(x) is methyl. In further or additionalembodiments, x is 1 and R^(x) and R^(x′) are methyl. In further oradditional embodiments, A is C(O)O—B¹, x is 1 and R^(x) and R^(x′) aremethyl.

In some embodiments, z is 0 and A is H. In further or additionalembodiments, y is 0, z is 0 and A is H. In further or additionalembodiments, R^(x) is not H. In further or additional embodiments, R^(x)and R^(x′) are not H.

In further or additional embodiments, R^(x) is optionally substitutedC₁₋₃ alkyl. In further or additional embodiments, R^(x) and R^(x′) areoptionally substituted C₁₋₃ alkyl. In further or additional embodiments,y is 0, z is 0, A is H and R^(x) is not H. In further or additionalembodiments, y is 0, z is 0, A is H and R^(x) and R^(x′) are not H. Infurther or additional embodiments, y is 0, z is 0, A is H and R^(x) isoptionally substituted C₁₋₃ alkyl. In further or additional embodiments,y is 0, z is 0, A is H and R^(x) and R^(x′) are optionally substitutedC₁₋₃ alkyl. In some embodiments, R^(x), R^(x′), R^(y), R^(y′), R^(z) andR^(z′) are each independently H. In further or additional embodiments,at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) is not H.In further or additional embodiments, at least two of R^(x), R^(x′),R^(y), R^(y′), R^(z) and R^(z′) are not H. In further or additionalembodiments, at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) andR^(z′) is optionally substituted C₁₋₃ alkyl. In further or additionalembodiments, at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) andR^(z′) is substituted C₁₋₃ alkyl. In further or additional embodiments,at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) is C₁₋₃alkyl. In further or additional embodiments, at least one of R^(x),R^(x′), R^(y), R^(y′), R^(z) and R^(z′) is optionally substitutedmethyl. In further or additional embodiments, at least one of R^(x),R^(x′), R^(y), R^(y′), R^(z) and R^(z′) is substituted methyl. Infurther or additional embodiments, at least one of R^(x), R^(x′), R^(y),R^(y′), R^(z) and R^(z′) is methyl. In further or additionalembodiments, at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) andR^(z′) is optionally substituted ethyl. In further or additionalembodiments, at least one of R^(x), R^(x′), R^(y), R^(y′), R^(z) andR^(z′) is substituted ethyl. In further or additional embodiments, atleast one of R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) is ethyl. Infurther or additional embodiments, R^(x) is optionally substituted C₁₋₃alkyl. In further or additional embodiments, R^(x) is substituted C₁₋₃alkyl. In further or additional embodiments, R^(x) is C₁₋₃ alkyl. Infurther or additional embodiments, R^(x) is optionally substitutedmethyl. In further or additional embodiments, R^(x) is substitutedmethyl. In further or additional embodiments, R^(x) is methyl. Infurther or additional embodiments, R^(x) is optionally substitutedethyl. In further or additional embodiments, R^(x) is substituted ethyl.In further or additional embodiments, R^(x) is ethyl. In further oradditional embodiments, R^(x) and R^(x′) are optionally substituted C₁₋₃alkyl. In further or additional embodiments, R^(x) and R^(x′) aresubstituted C₁₋₃ alkyl. In further or additional embodiments, R^(x) andR^(x′) are C₁₋₃ alkyl. In some embodiments, x, y, and z are each 1 andR^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each H.

In some embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) andR^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S, andwherein said ring may be optionally fused to 1 or 2 additionaloptionally substituted, aromatic or non-aromatic, 5-, 6- or 7-memberedrings, optionally comprising 1 or 2 heteroatoms selected from O, N andS. In further or additional embodiments, R^(x) and R^(x′) together withthe carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 3-7 membered ring, optionallycomprising 1 or 2 heteroatoms selected from O, N and S, and wherein saidring may be optionally fused to 1 or 2 additional optionallysubstituted, aromatic or non-aromatic, 5-, 6- or 7-membered rings,optionally comprising 1 or 2 heteroatoms selected from O, N and S. Infurther or additional embodiments, R^(y) and R^(y′) together with thecarbon atoms to which they are attached, form an optionally substituted,aromatic or non-aromatic, 3-7 membered ring, optionally comprising 1 or2 heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In further or additionalembodiments, R^(z) and R^(z′) together with the carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In further or additionalembodiments, R^(x) and R^(y) together with the carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In further or additionalembodiments, R^(y) and R^(z) together with the carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In further or additionalembodiments, R^(x) and R^(z) together with the carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S.

In some embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) andR^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S. Infurther or additional embodiments, the ring is a 3-membered ring. Infurther or additional embodiments, the ring is a 4-membered ring. Infurther or additional embodiments, the ring is a 5-membered ring. Infurther or additional embodiments, the ring is a 6-membered ring. Infurther or additional embodiments, the ring is a 7-membered ring. Infurther or additional embodiments, the ring does not comprise anyheteroatoms. In further or additional embodiments, the ring comprises 1heteroatom. In further or additional embodiments, the ring comprises 1oxygen atom. In further or additional embodiments, the ring comprises 1sulfur atom. In further or additional embodiments, the ring comprises 1nitrogen atom. In further or additional embodiments, the ring comprises2 heteroatoms. In further or additional embodiments, the ring isunsubstituted. In further or additional embodiments, the ring comprisesat least one substituent. In further or additional embodiments, the ringcomprises at least two substituents. In further or additionalembodiments, the ring comprises at least three substituents. In furtheror additional embodiments, the ring is non-aromatic. In further oradditional embodiments, the ring is aromatic.

In further or additional embodiments, R^(x) and R^(x′) together with thecarbon atoms to which they are attached, form an optionally substituted,non-aromatic 3-6 membered ring. In further or additional embodiments,R^(x) and R^(x′) together with the carbon atoms to which they areattached, form an optionally substituted, non-aromatic 3 membered ring.In further or additional embodiments, R^(x) and R^(x′) together with thecarbon atoms to which they are attached, form an optionally substituted,non-aromatic 4 membered ring. In further or additional embodiments,R^(x) and R^(x′) together with the carbon atoms to which they areattached, form an optionally substituted, non-aromatic 5 membered ring.In further or additional embodiments, R^(x) and R^(x′) together with thecarbon atoms to which they are attached, form an optionally substituted,non-aromatic 6 membered ring. In further or additional embodiments,R^(y) and R^(y′) together with the carbon atoms to which they areattached, form an optionally substituted, non-aromatic 3-6 memberedring. In further or additional embodiments, R^(y) and R^(y′) togetherwith the carbon atoms to which they are attached, form an optionallysubstituted, non-aromatic 3 membered ring. In further or additionalembodiments, R^(y) and R^(y′) together with the carbon atoms to whichthey are attached, form an optionally substituted, non-aromatic 4membered ring. In further or additional embodiments, R^(y) and R^(y′)together with the carbon atoms to which they are attached, form anoptionally substituted, non-aromatic 5 membered ring. In further oradditional embodiments, R^(y) and R^(y′) together with the carbon atomsto which they are attached, form an optionally substituted, non-aromatic6 membered ring. In further or additional embodiments, R^(x) and R^(y)together with the carbon atoms to which they are attached, form anoptionally substituted, non-aromatic 3-6 membered ring. In further oradditional embodiments, R^(x) and R^(y) together with the carbon atomsto which they are attached, form an optionally substituted, non-aromatic3 membered ring. In further or additional embodiments, R^(x) and R^(y)together with the carbon atoms to which they are attached, form anoptionally substituted, non-aromatic 4 membered ring. In further oradditional embodiments, R^(x) and R^(y) together with the carbon atomsto which they are attached, form an optionally substituted, non-aromatic5 membered ring. In further or additional embodiments, R^(x) and R^(y)together with the carbon atoms to which they are attached, form anoptionally substituted, non-aromatic 6 membered ring.

In some embodiments, R^(b), R^(c), R^(d), R^(e) and R^(f) are eachindependently H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′,S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl; wherein R′ is methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl orcyclopropylmethyl; R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl or cyclopropylmethyl; or R′ and R″ together with thenitrogen atom to which they are attached form an optionally substituted,saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring. Infurther or additional embodiments, at least of one of R^(b), R^(c),R^(d), R^(e) and R^(f) is not H. In further or additional embodiments,two of R^(b), R^(c), R^(d), R^(e) and R^(f) are not H. In further oradditional embodiments, three of R^(b), R^(c), R^(d), R^(e) and R^(f)are not H. In further or additional embodiments, at least of one ofR^(b), R^(c), R^(d), R^(e) and R^(f) is H. In further or additionalembodiments, at least of one of R^(b), R^(c), R^(d), R^(e) and R^(f) isH and at least one is not H. In further or additional embodiments,R^(b), R^(c), R^(d), R^(e) and R^(f) are each independently H, Cl, CF₃,alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OR′ or CO₂H.

In further or additional embodiments, R^(d) is not H. In further oradditional embodiments, R^(d) is alkyl, cycloalkyl or cyclopropylmethyl.In further or additional embodiments, R^(d) is alkyl. In further oradditional embodiments, R^(d) is methyl or ethyl. In further oradditional embodiments, R^(d) is cycloalkyl. In further or additionalembodiments, R^(d) is cycloproyl, cyclobutyl or cyclopentyl.

In some embodiments, R^(b) and R^(c), or R^(c) and R^(d), or R^(d) andR^(e), or R^(e) and R^(f) together with the two carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S; and wherein the optionalsubstituents are each independently F, Cl, Br, I, CF₃, CN, alkyl,cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl.

In some embodiments, R^(b) and R^(c) together with the two carbon atomsto which they are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S; and wherein the optionalsubstituents are each independently F, Cl, Br, I, CF₃, CN, alkyl,cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl.

In some embodiments, R^(b) and R^(c) together with the two carbon atomsto which they are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S.

In some embodiments, R^(b) and R^(c) together with the two carbon atomsto which they are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S. In some embodiments, R^(b) andR^(c) together with the two carbon atoms to which they are attached,form an optionally substituted, aromatic or non-aromatic, 5-, 6- or7-membered ring. In some embodiments, R^(b) and R^(c) together with thetwo carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 5-membered ring. In someembodiments, R^(b) and R^(c) together with the two carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 6-membered ring. In some embodiments, R^(b) and R^(c)together with the two carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 7-membered ring. Insome embodiments, R^(b) and R^(c) together with the two carbon atoms towhich they are attached, form a substituted, aromatic or non-aromatic,5-, 6- or 7-membered ring. In some embodiments, R^(b) and R^(c) togetherwith the two carbon atoms to which they are attached, form asubstituted, aromatic, 5-, 6- or 7-membered ring. In some embodiments,R^(b) and R^(c) together with the two carbon atoms to which they areattached, form a substituted, aromatic, 5-membered ring. In someembodiments, R^(b) and R^(c) together with the two carbon atoms to whichthey are attached, form a substituted, aromatic, 6-membered ring. Insome embodiments, R^(b) and R^(c) together with the two carbon atoms towhich they are attached, form a substituted, aromatic, 7-membered ring.In some embodiments, R^(b) and R^(c) together with the two carbon atomsto which they are attached, form a substituted, non-aromatic, 5-, 6- or7-membered ring. In some embodiments, R^(b) and R^(c) together with thetwo carbon atoms to which they are attached, form a substituted,non-aromatic, 5-membered ring. In some embodiments, R^(b) and R^(c)together with the two carbon atoms to which they are attached, form asubstituted, non-aromatic, 6-membered ring. In some embodiments, R^(b)and R^(c) together with the two carbon atoms to which they are attached,form a substituted, non-aromatic, 7-membered ring. In further oradditional embodiments, R^(b) and R^(c), together with the two carbonatoms to which they are attached, form an optionally substituted,aromatic or non-aromatic, 6-membered ring, comprising 1 heteroatomselected from O, N and S. In further or additional embodiments, R^(b)and R^(c), together with the two carbon atoms to which they areattached, form an optionally substituted, aromatic or non-aromatic, 5-,6- or 7-membered ring, comprising 1 oxygen atom. In further oradditional embodiments, R^(b) and R^(c), together with the two carbonatoms to which they are attached, form an optionally substituted,aromatic or non-aromatic, 6-membered ring, comprising 1 sulfur atom. Infurther or additional embodiments, R^(b) and R^(c), together with thetwo carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 6-membered ring, comprising 1nitrogen atom. In further or additional embodiments, R^(b) and R^(c),together with the two carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 6-membered ring,comprising 2 heteroatoms selected from O, N and S. In further oradditional embodiments, R^(b) and R^(c), together with the two carbonatoms to which they are attached, form an optionally substituted,aromatic or non-aromatic, 6-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S. In further or additionalembodiments, R^(b) and R^(c), together with the two carbon atoms towhich they are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S. In further or additionalembodiments, R^(b) and R^(c), together with the two carbon atoms towhich they are attached, form an optionally substituted, aromatic ornon-aromatic, 6-membered ring, optionally comprising 1 or 2 heteroatomsselected from O, N and S. In further or additional embodiments, R^(b)and R^(c), together with the two carbon atoms to which they areattached, form an optionally substituted, aromatic or non-aromatic, 5-,6- or 7-membered ring, optionally comprising 1 nitrogen atom. In furtheror additional embodiments, R^(b) and R^(c), together with the two carbonatoms to which they are attached, form an optionally substituted,aromatic or non-aromatic, 6-membered ring, optionally comprising 1nitrogen atom. In some embodiments, R^(c) and R^(d) together with thetwo carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 5-, 6- or 7-membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S, andwherein said ring may be optionally fused to 1 or 2 additionaloptionally substituted, aromatic or non-aromatic, 5-, 6- or 7-memberedrings, optionally comprising 1 or 2 heteroatoms selected from O, N andS; and wherein the optional substituents are each independently F, Cl,Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″,OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl orheteroaryl.

In further or additional embodiments, R^(c) and R^(d), together with thetwo carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 5-, 6- or 7-membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S. Infurther or additional embodiments, R^(c) and R^(d), together with thetwo carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 6-membered ring, optionallycomprising 1 or 2 heteroatoms selected from O, N and S.

Another aspect of the invention provides for a compound of formula(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I)or (II-J), or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

wherein:

-   -   W is O, S, S(O), S(O)₂, NH, N(optionally substituted alkyl),        CH₂, CH₂O, CH₂S or CH₂NH;    -   R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH, NO₂, NH₂,        NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃,        CO₂-alkyl, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkoxy, optionally substituted        S-alkyl, optionally substituted cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl or        optionally substituted heteroaryl;    -   a is 0, 1 or 2;    -   R^(a) is H or optionally substituted C₁₋₃ alkyl;    -   R^(a′) is H or optionally substituted C₁₋₃ alkyl; or    -   R^(a) and R^(a′) together with the carbon atom to which they are        attached form a 3-, 4-, 5- or 6-membered ring, optionally        comprising 1 or 2 heteroatoms selected from O, N and S;    -   R^(d), R^(e), R^(f), R^(g) and R^(h) are each independently H,        F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,        aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring;    -   R³ is        —(CR^(x)R^(x′))_(x)—(CR^(y)R^(y′))_(y)—(CR^(z)R^(z))_(z)-A;        wherein    -   x is 0 or 1;    -   y is 0 or 1;    -   z is 0 or 1;    -   R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each        independently H, F, Cl, Br, or optionally substituted C₁₋₃        alkyl; or    -   R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), or        R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together        with the carbon atoms to which they are attached, form an        optionally substituted, aromatic or non-aromatic, 3-7 membered        ring, optionally comprising 1 or 2 heteroatoms selected from O,        N and S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   A is H, C(O)O—B¹ or C(O)NH—B²; wherein    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation;    -   B² is H or optionally substituted C₁₋₆ alkyl; and wherein        all alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and        heteroaryl moieties may be optionally further substituted.

In some embodiments, the invention provides for compounds of formula(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I)or (II-J). In further or additional embodiments, the invention providesfor metabolites of a compound of formula (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable salts of compounds of formula (II-A), (II-B), (II-C), (II-D),(II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable solvates of compounds of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable polymorphs of compounds of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable esters of compounds of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable tautomers of compounds of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I) or (II-J). In further oradditional embodiments, the invention provides for pharmaceuticallyacceptable prodrugs of compounds of formula (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), (II-H), (II-I) or (II-J).

In some embodiments, the invention provides for compounds of formula(II-A). In some embodiments, the invention provides for compounds offormula (II-B). In some embodiments, the invention provides forcompounds of formula (II-C). In some embodiments, the invention providesfor compounds of formula (II-D). In some embodiments, the inventionprovides for compounds of formula (II-E). In some embodiments, theinvention provides for compounds of formula (II-F). In some embodiments,the invention provides for compounds of formula (II-G). In someembodiments, the invention provides for compounds of formula (II-H). Insome embodiments, the invention provides for compounds of formula(II-I). In some embodiments, the invention provides for compounds offormula (II-J).

In further or additional embodiments, R^(d), R^(e), R^(f), R^(g) andR^(h) are each independently H, Cl, CF₃, alkyl, cycloalkyl,cyclopropylmethyl, NH₂, NHR′, NR′R″, OR′ or CO₂H. In some embodiments,at least of one of R^(d), R^(e), R^(f), R^(g) and R^(h) is not H. Infurther or additional embodiments, two of R^(d), R^(e), R^(f), R^(g) andR^(h) are not H. In further or additional embodiments, three of R^(d),R^(e), R^(f), R^(g) and R^(h) are not H. In further or additionalembodiments, at least of one of R^(d), R^(e), R^(f), R^(g) and R^(h) isH. In further or additional embodiments, at least of one of R^(d),R^(e), R^(f), R^(g) and R^(h) is H and at least one is not H. In furtheror additional embodiments, R^(d) is not H. In further or additionalembodiments, R^(d) is optionally substituted alkyl, cycloalkyl orcyclopropylmethyl. In further or additional embodiments, R^(d) issubstituted alkyl, cycloalkyl or cyclopropylmethyl. In further oradditional embodiments, R^(d) is alkyl, cycloalkyl or cyclopropylmethyl.In further or additional embodiments, R^(d) is alkyl. In further oradditional embodiments, R^(d) is methyl or ethyl. In further oradditional embodiments, R^(d) is cycloalkyl. In further or additionalembodiments, R^(d) is cycloproyl, cyclobutyl or cyclopentyl.

Another aspect of the invention provides for a compound of formula(IIK), (IIL), (IIM), (IIN), (IIO) or (IIP), or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof:

wherein:

-   -   R^(g) and R^(h) are each independently H, F, Cl, Br, I, CF₃, CN,        alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′,        SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or        heteroaryl; wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring.

In some embodiments, the invention provides compounds of formula (II-K),(II-L), (II-M), (II-N), (II-O) or (II-P). In some embodiments, theinvention provides for metabolites of compounds of formula (II-K),(II-L), (II-M), (II-N), (II-O) or (II-P). In some embodiments, theinvention provides for pharmaceutically acceptable salts of compounds offormula (II-K), (II-L), (II-M), (II-N), (II-O) or (II-P). In someembodiments, the invention provides for pharmaceutically acceptablesolvates of compounds of formula (II-K), (II-L), (II-M), (II-N), (II-O)or (II-P). In some embodiments, the invention provides forpharmaceutically acceptable polymorphs of compounds of formula (II-K),(II-L), (II-M), (II-N), (II-O) or (II-P). In some embodiments, theinvention provides for pharmaceutically acceptable esters of compoundsof formula (II-K), (II-L), (II-M), (II-N), (II-O) or (II-P). In someembodiments, the invention provides for pharmaceutically acceptabletautomers of compounds of formula (II-K), (II-L), (II-M), (II-N), (II-O)or (II-P). In some embodiments, the invention provides forpharmaceutically acceptable prodrugs of compounds of formula (II-K),(II-L), (II-M), (II-N), (II-O) or (II-P). In some embodiments, theinvention provides compounds of formula (II-K). In some embodiments, theinvention provides compounds of formula (II-L). In some embodiments, theinvention provides compounds of formula (II-M). In some embodiments, theinvention provides compounds of formula (II-N). In some embodiments, theinvention provides compounds of formula (II-O). In some embodiments, theinvention provides compounds of formula (II-P).

In other embodiments, the invention provides compounds of formula(II-Q), or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

wherein:

-   -   R^(i) and R^(j) are each independently H, F, Cl, Br, I, CF₃, CN,        alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′,        SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or        heteroaryl; wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring.

In further or additional embodiments, W is O or S. In further oradditional embodiments, W is S. In further or additional embodiments, R¹is H, F, Cl, Br, CH₂F, CF₂H, CF₃, NH₂, CH₃ or optionally substitutedphenyl. In further or additional embodiments, a is 0. In further oradditional embodiments, R^(a) is H and R^(a′) is H. In further oradditional embodiments, W is O or S; R¹ is H, F, Cl, Br, CH₂F, CF₂H,CF₃, NH₂, CH₃ or optionally substituted phenyl; and a is 0.

Another aspect of the invention provides a method for decreasing uricacid levels in one or more tissues or organs of a subject in need ofdecreased uric acid levels, comprising administering to the subject auric acid level decreasing amount of a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof. In some embodiments, the subject has adisorder characterized by an abnormally high content of uric acid in oneor more tissues or organs of the subject.

In further or additional embodiments, the disorder is characterized byoverproduction of uric acid, low excretion of uric acid, tumor lysis, ablood disorder or a combination thereof. In further or additionalembodiments, the blood disorder is polycythemia or myeloid metaplasia.In further or additional embodiments, the subject in need of decreasedserum uric acid levels is suffering from gout, a recurrent gout attack,gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis. In further or additional embodiments, the uricacid levels are decreased by at least about 1% in one or more tissues ororgans of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 2% in one or more tissues ororgans of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 5% in one or more tissues ororgans of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 10% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 12% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 15% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 20% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 25% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 30% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 40% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 50% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 60% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 70% in one or more tissuesor organs of the subject. In further or additional embodiments, the uricacid levels are decreased by at least about 75% in one or more tissuesor organs of the subject.

In further or additional embodiments, the tissue or organ is blood. Infurther or additional embodiments, the blood uric acid level isdecreased by at least about 0.5 mg/dL. In further or additionalembodiments, the blood uric acid level is decreased by at least about 1mg/dL. In further or additional embodiments, the blood uric acid levelis decreased by at least about 2 mg/dL.

In further or additional embodiments, one or more metabolites of acompound disclosed herein is administered. In further or additionalembodiments, one or more pharmaceutically acceptable salts of a compounddisclosed herein is administered. In further or additional embodiments,one or more pharmaceutically acceptable solvates of a compound disclosedherein is administered. In further or additional embodiments, one ormore pharmaceutically acceptable polymorphs of a compound disclosedherein is administered. In further or additional embodiments, one ormore pharmaceutically acceptable of a esters compound of formula (II) isadministered. In further or additional embodiments, one or morepharmaceutically acceptable tautomers of a compound disclosed herein isadministered. In further or additional embodiments, one or morepharmaceutically acceptable prodrugs of a compound disclosed herein isadministered.

Yet another aspect of the invention provides a method for reducing uricacid production, increasing uric acid excretion or both in a subject,comprising administering to the subject a compound disclosed herein or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Another aspect of the invention provides a method for treating orpreventing hyperuricemia in a subject comprising administering to thesubject an effective amount of a compound disclosed herein, or ametabolite, pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof, wherein said amount is effective inlowering the level of uric acid.

Another aspect of the invention provides a method of treating a subjectsuffering from a condition characterized by abnormal tissue or organlevels of uric acid comprising administering to the subject an effectiveamount of a compound disclosed herein or a metabolite, pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.In some embodiments, the condition is characterized by low tissue levelsof uric acid. In further or additional embodiments, the condition ischaracterized by high tissue levels of uric acid. In further oradditional embodiments, the condition is selected from gout, a recurrentgout attack, gouty arthritis, hyperuricaemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosis. In further or additionalembodiments, the condition is gout. In further or additionalembodiments, the condition is joint inflammation. In further oradditional embodiments, the joint inflammation is caused by deposits ofuric acid crystals in the joint. In further or additional embodiments,the uric acid crystals are deposited in the joint fluid (synovial fluid)or joint lining (synovial lining). In other embodiments, the methodfurther comprises administering an agent effective for the treatment ofthe condition. In further or additional embodiments, the agent iseffective in reducing tissue levels of uric acid. In further oradditional embodiments, the agent is a nonsteroidal anti-inflammatorydrugs (NSAIDs), colchicine, a corticosteroid, adrenocorticotropichormone (ACTH), probenecid, sulfinpyrazone or allopurinol. In further oradditional embodiments, the agent is allopurinol.

Yet another aspect of the invention provides a method for preventing acondition characterized by abnormal tissue levels of uric acid in asubject at increased risk of developing the condition, comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof. In some embodiments, thecondition is selected from gout, a recurrent gout attack, goutyarthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis.

Another aspect of the invention provides a method for treating gout, arecurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosisin a subject comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Another aspect of the invention provides a method for treating gout in asubject comprising administering to the subject an effective amount of acompound disclosed herein or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof. In someembodiments, the method further comprises administering an agenteffective for the treatment of the gout. In further or additionalembodiments, the agent is allopurinol.

Another aspect of the invention provides a method for preventing theformation or reducing the size of tophi/tophus in a subject, comprisingadministering to the subject an effective amount of a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Another aspect of the invention provides a method for decreasing uricacid levels in one or more tissues or organs of a subject comprisingadministering to the subject a uric acid level decreasing amount of acompound disclosed herein or a metabolite, pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof, whereinthe reduction in uric acid levels results in a reduction in hypertensionor cardiovascular events.

Another aspect of the invention provides a method for treatinghypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in asubject comprising administering to the subject a compound disclosedherein or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof.

Other aspects of the invention provide a pharmaceutical compositionuseful for decreasing uric acid levels comprising:

-   i) a sufficient amount of a compound disclosed herein or a    metabolite, pharmaceutically acceptable salt, solvate, polymorph,    ester, tautomer or prodrug thereof, to decrease uric acid levels;    and-   ii) optionally one or more pharmaceutically acceptable carriers.

Other aspects of the invention provide a pharmaceutical compositionuseful for reducing hypertension or cardiovascular events comprising:

-   i) a sufficient amount of a compound disclosed herein or a    metabolite, pharmaceutically acceptable salt, solvate, polymorph,    ester, tautomer or prodrug thereof to decrease uric acid levels; and-   ii) optionally one or more pharmaceutically acceptable carriers.

Other aspects of the invention provide a pharmaceutical compositioncomprising:

-   i) a compound disclosed herein or a metabolite, pharmaceutically    acceptable salt, solvate, polymorph, ester, tautomer or prodrug    thereof;-   ii) allopurinol; and-   iii) optionally one or more pharmaceutically acceptable carriers.

Other aspects of the invention provide a pharmaceutical compositionuseful in the treatment of edema and hypertension which also maintainsuric acid levels at pretreatment levels or causes a decrease in uricacid levels comprising:

-   i) an antihypertensive agent;-   ii) a uric acid level maintaining or lowering amount of a compound    of the formula (II) or a metabolite, pharmaceutically acceptable    salt, solvate, polymorph, ester, tautomer or prodrug thereof; and-   iii) optionally one or more pharmaceutically acceptable carriers.

Other aspects of the invention provide a pharmaceutical compositionuseful in the treatment of cancer which also maintains uric acid levelsat pretreatment levels or causes a decrease in uric acid levelscomprising:

-   i) an anticancer agent;-   ii) a uric acid level maintaining or lowering amount of a compound    of the formula (II) or a metabolite, pharmaceutically acceptable    salt, solvate, polymorph, ester, tautomer or prodrug thereof; and-   iii) optionally one or more pharmaceutically acceptable carriers.

Other aspects of the invention provide a pharmaceutical compositionuseful for reducing the side effects of chemotherapy in a cancerpatient, comprising:

-   i) a uric acid level maintaining or lowering amount of a compound of    the formula (II) or a metabolite, pharmaceutically acceptable salt,    solvate, polymorph, ester, tautomer or prodrug thereof; and-   ii) optionally one or more pharmaceutically acceptable carriers;    wherein said side effects are related to elevated uric acid levels.

The present invention provides methods for modulating the content ofuric acid in a subject comprising administrating to the subject aneffective content-modulating amount of a compound disclosed herein. Theinvention also provides pharmaceutical compositions and methods fortreating disorders of uric acid metabolism and resulting ailments in asubject, such as gout, gouty arthritis, inflammatory arthritis, kidneydisease, nephrolithiasis (kidney stones), joint inflammation, depositionof urate crystals in joints, urolithiasis (formation of calculus in theurinary tract), deposition of urate crystals in renal parenchyma,Lesch-Nyhan syndrome, and/or Kelley-Seegmiller syndrome.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is H, F, Cl, Br, I, —CH₂F, —CF₂H, —CF₃, —CN, —OH, —NO₂, —NH₂,        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —CO₂—C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,        C₁₋₄S-alkyl, C₃₋₆cycloalkyl, optionally substituted        C₁₋₆heterocycloalkyl, optionally substituted phenyl, or        optionally substituted 5 or 6 membered heteroaryl;    -   R^(d) is F, Cl, Br, I, CF₃, aryl, heteroaryl, CN, NO₂, NH₂,        NHR′, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′,        CONR′R″, SO₃H, SO₃R′, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or        S(O)₂NR′R″;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) and R^(x′) are each independently H, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted heteroalkyl,        optionally substituted heteroalkenyl, optionally substituted        heteroalkynyl, optionally substituted cycloalkyl, optionally        substituted cycloalkenyl, optionally substituted heterocyclyl,        optionally substituted aryl, optionally substituted heteroaryl,        halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,        COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, or S(O)₂NR′R″; or    -   R^(x) and R^(x′) together with the carbon atom to which they are        attached, form an optionally substituted non-aromatic 3-7        membered ring, optionally comprising 1 or 2 heteroatoms selected        from O, N and S;    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and        each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x′) areindependently H, F, CF₃, or methyl. In some embodiments, R^(x) is F andR^(x1) is F. In some embodiments, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, or CH₃. In some embodiments, R¹ is Br. In some embodiments, R^(d)is H, F, Cl, Br, I, CF₃, or CN.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is H, F, Cl, Br, I, —CH₂F, —CF₂H, —CF₃, —CN, —OH, —NO₂, —NH₂,        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —CO₂—C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,        C₁₋₄S-alkyl, C₃₋₆cycloalkyl, optionally substituted        C₁₋₆heterocycloalkyl, optionally substituted phenyl, or        optionally substituted 5 or 6 membered heteroaryl;    -   R^(d) is H, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NO₂, NH₂, NHR′, NR′R″, OH,        OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        SO₃R′, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) is F, Cl, Br, I, or C₁-C₃ fluoroalkyl;    -   R^(x′) is independently H, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted heteroalkyl, optionally substituted        heteroalkenyl, optionally substituted heteroalkynyl, optionally        substituted cycloalkyl, optionally substituted cycloalkenyl,        optionally substituted heterocyclyl, optionally substituted        aryl, optionally substituted heteroaryl, halo, CN, NH₂, NHR′,        NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′,        CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″; and    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and    -   each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x′) areindependently H, F, methyl, or CF₃. In some embodiments, R^(x) is F andR^(x1) is F. In some embodiments, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, or CH₃. In some embodiments, R¹ is Br. In some embodiments, R^(d)is F, Cl, Br, I, CF₃, or CN.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is halo or haloalkyl;    -   R^(d) is H;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) and R^(x′) are each independently H, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted heteroalkyl,        optionally substituted heteroalkenyl, optionally substituted        heteroalkynyl, optionally substituted cycloalkyl, optionally        substituted cycloalkenyl, optionally substituted heterocyclyl,        optionally substituted aryl, optionally substituted heteroaryl,        halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,        COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, or S(O)₂NR′R″; or    -   R^(x) and R^(x′) together with the carbon atom to which they are        attached, form an optionally substituted non-aromatic 3-7        membered ring, optionally comprising 1 or 2 heteroatoms selected        from O, N and S;    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and    -   each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x1) areindependently H, F, CF₃, or methyl. In some embodiments, R^(x) is methyland R^(x1) is methyl.

Disclosed herein, in certain embodiments, is a method of treating goutcomprising administering to an individual in need thereof atherapeutically effective amount of a compound disclosed herein.

Disclosed herein, in certain embodiments, is a method of treatinghyperuricemia in an individual with comprising administering to anindividual in need thereof a therapeutically effective amount of acompound disclosed herein.

Disclosed herein, in certain embodiments, is a pharmaceuticalcomposition comprising a therapeutically effective amount of a compounddisclosed herein and a pharmaceutically acceptable excipient. In someembodiments, the therapeutically effective amount of the compound is anamount therapeutically effective for treating gout.

Pharmaceutically acceptable salts of any compound described hereininclude benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, zinc, benethamine, clemizole,diethyliunine, piperazine, tromethamine, barium, and bismuth salts. Insome embodiments, B¹ of any compound described herein is a benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, benethamine, clemizole, diethyliunine, piperazine, tromethamine,barium, or bismuth cation.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows a graph of mean plasma concentration of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(Eg. 1) at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) postdosing, as released by in vivo metabolism of2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid (Eg. 3),(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoicacid (Eg. 8) and(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoicacid (Eg. 9), after PO dosing to male rats (3 mg/kg).

FIG. 2 shows a graph of mean plasma concentrations of2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid (Eg. 3) and example 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

FIG. 3 shows a graph of mean plasma concentrations of(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-iH-imidazol-2-ylthio)acetamido)propanoicacid (Eg. 8) and example 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

FIG. 4 shows a graph of mean plasma concentrations of(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoicacid (Eg. 9) and example 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

DETAILED DESCRIPTION OF THE INVENTION

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized.

While preferred embodiments of the present invention have been shown anddescribed herein, such embodiments are provided by way of example only.Various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, without limitation, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference for the purposes stated herein.

Methods: Aberrant Uric Acid Levels

The present invention also provides methods useful for diseases ordiseases related to aberrant uric acid levels. The method includesadministering an effective amount of a composition as described hereinto a subject with aberrant levels of uric acid so as to restore uricacid levels to acceptable levels or non-aberrant levels. The presentinvention also provides methods useful for decreasing uric acid levelsin one or more tissues or organs of a subject in need of decreased uricacid levels, comprising administering to the subject a uric acid leveldecreasing amount of a composition as described herein. The presentinvention also provides methods useful for reducing uric acidproduction, increasing uric acid excretion or both in a subject,comprising administering to the subject an effective amount of acomposition as described herein. The present invention also providesmethods useful for treating or preventing hyperuricemia in a subjectcomprising administering to the subject an effective amount of acomposition as described herein. The present invention also providesmethods useful for treating a subject suffering from a conditioncharacterized by abnormal tissue or organ levels of uric acid comprisingadministering to the subject an effective amount of a composition asdescribed herein The present invention also provides methods useful fortreating a subject suffering from gout, a recurrent gout attack, goutyarthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis or sarcoidosis, comprising administering to the subject aneffective amount of a composition as described herein. The presentinvention also provides methods useful for preventing a conditioncharacterized by abnormal tissue levels of uric acid in a subject atincreased risk of developing the condition, comprising administering tothe subject an effective amount of a composition as described herein.The present invention also provides methods useful for treating gout, arecurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis or sarcoidosisin a subject comprisingadministering to the subject an effective amount of a composition asdescribed herein. The present invention also provides methods useful fortreating gout in a subject comprising administering to the subject aneffective amount of a composition as described herein. The presentinvention also provides methods useful for preventing the formation orreducing the size of tophi/tophus in a subject, comprising administeringto the subject an effective amount of a composition as described herein.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereis a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet or other appropriatereference source. Reference thereto evidences the availability andpublic dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. It should alsobe noted that use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes”, and “included” is not limiting.

Definition of standard chemistry terms are found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, IR andUV/Vis spectroscopy and pharmacology, are employed.

Where substituent groups are specified by their conventional chemicalformulas, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left. As a non-limiting example, —CH₂O— isequivalent to —OCH₂—.

Unless otherwise noted, the use of general chemical terms, such asthough not limited to “alkyl,” “amine,” “aryl,” are equivalent to theiroptionally substituted forms. For example, “alkyl,” as used herein,includes optionally substituted alkyl.

In some embodiments, the compounds presented herein possess one or morestereocenters. In some embodiments, each center exists in the R or Sconfiguration, or combinations thereof. In some embodiments, thecompounds presented herein possess one or more double bonds. In someembodiments, each double bond exists in the E (trans) or Z (cis)configuration, or combinations thereof. Presentation of one particularstereoisomer, regioisomer, diastereomer, enantiomer or epimer should beunderstood to include all possible stereoisomers, regioisomers,diastereomers, enantiomers or epimers and mixtures thereof. Thus, thecompounds presented herein include all separate configurationalstereoisomeric, regioisomeric, diastereomeric, enantiomeric, andepimeric forms as well as the corresponding mixtures thereof. Techniquesfor inverting or leaving unchanged a particular stereocenter, and thosefor resolving mixtures of stereoisomers are found, for example, Furnisset al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.

The terms “moiety”, “chemical moiety”, “group” and “chemical group”, asused herein refer to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “reactant,” as used herein, refers to a nucleophile orelectrophile used to create covalent linkages.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl”. Further, anoptionally substituted group means un-substituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), mono-substituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃, —CFHCHF₂, etc). Withrespect to any group containing one or more substituents, such groupsare not intended to introduce any substitution or substitution patterns(e.g., substituted alkyl includes optionally substituted cycloalkylgroups, which in turn are defined as including optionally substitutedalkyl groups, potentially ad infinitum) that are sterically impracticaland/or synthetically non-feasible. Thus, any substituents describedshould generally be understood as having a maximum molecular weight ofabout 1,000 daltons, and more typically, up to about 500 daltons (exceptin those instances where macromolecular substituents are clearlyintended, e.g., polypeptides, polysaccharides, polyethylene glycols,DNA, RNA and the like). “Substituted” groups are optionally substitutedwith, by way of non-limiting example, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, alkylheteroaryl, alkylcycloalkyl, alkylcycloalkenyl,alkylheterocyclyl, alkylaryl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl,heteroalkylheterocyclyl, heteroalkylaryl, cycloheteroalkylheteroalkyl,cycloalkenylheteroalkyl, heterocyclylheteroalkyl, arylheteroalkyl,heteroarylheteroalkyl, heteroarylheteroalkyl, halo, CN, No₂, NR₂, OR,SR, C(O)R, CO₂R, CONR₂, SO₃R, S(O)₂R, S(O)₂NR₂, or the like, whereineach R is independently alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, heteroaryl, or the like, or wherein two R groups on the same atom,taken together, form a 3-10 membered heterocyclic ring.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as theranges C₁-C₂ and C₁-C₃. Thus, by way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl group,i.e., the alkyl group is selected from among methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means 1 carbonatom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10carbon atoms.

The term “lower” as used herein in combination with terms such as alkyl,alkenyl or alkynyl, (i.e. “lower alkyl”, “lower alkenyl” or “loweralkynyl”) refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about six carbon atoms, more preferably one to threecarbon atoms. Examples include, but are not limited to methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl.

The term “hydrocarbon” as used herein, alone or in combination, refersto a compound or chemical group containing only carbon and hydrogenatoms.

The terms “heteroatom” or “hetero” as used herein, alone or incombination, refer to an atom other than carbon or hydrogen. Heteroatomsinclude, but are not limited to, oxygen, nitrogen, sulfur, phosphorous,silicon, selenium and tin, but are not limited to these atoms. Where twoor more heteroatoms are present, in some embodiments, the two or moreheteroatoms are the same as each another. Where two or more heteroatomsare present, in some embodiments, the two or more heteroatoms aredifferent from the others.

The term “alkyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain saturated hydrocarbon monoradical having from one toabout ten carbon atoms, more preferably one to six carbon atoms.Examples include, but are not limited to methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that: in some embodiments, the alkyl group consistsof 1 carbon atom; in some embodiments, 2 carbon atoms; in someembodiments, 3 carbon atoms; in some embodiments, 4 carbon atoms; insome embodiments, 5 carbon atoms; in some embodiments, 6 carbon atoms.The present definition also covers the occurrence of the term “alkyl”where no numerical range is designated. In certain instances, “alkyl”groups described herein include linear and branched alkyl groups,saturated and unsaturated alkyl groups, and cyclic and acyclic alkylgroups.

The term “alkylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, alkyl. Examplesinclude, but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), isopropylene (—CH(CH₃)CH₂—) and the like.

The term “alkenyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbondouble-bonds and having from two to about ten carbon atoms, morepreferably two to about six carbon atoms. The group includes either thecis or trans conformation about the double bond(s), and should beunderstood to include both isomers. Examples include, but are notlimited to ethenyl (—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl[—C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like. Whenever it appearsherein, a numerical range such as “C₂-C₆ alkenyl” or “C₂₋₆ alkenyl”,means that: in some embodiments, the alkenyl group consists of 2 carbonatoms; in some embodiments, 3 carbon atoms; in some embodiments, 4carbon atoms; in some embodiments, 5 carbon atoms; in some embodiments,6 carbon atoms. The present definition also covers the occurrence of theterm “alkenyl” where no numerical range is designated.

The term “alkenylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical alkenyl. Examplesinclude, but are not limited to ethenylene (—CH═CH—), the propenyleneisomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

The term “alkynyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbontriple-bonds and having from two to about ten carbon atoms, morepreferably from two to about six carbon atoms. Examples include, but arenot limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and thelike. Whenever it appears herein, a numerical range such as “C₂-C₆alkynyl” or “C₂₋₆ alkynyl”, means: in some embodiments, the alkynylgroup consists of 2 carbon atoms; in some embodiments, 3 carbon atoms;in some embodiments, 4 carbon atoms; in some embodiments, 5 carbonatoms; in some embodiments, 6 carbon atoms. The present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated.

The term “alkynylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical, alkynyl.Examples include, but are not limited to ethynylene (—C≡C—),propargylene (—CH₂—C≡C—) and the like.

The term “aliphatic” as used herein, alone or in combination, refers toan optionally substituted, straight-chain or branched-chain, non-cyclic,saturated, partially unsaturated, or fully unsaturated nonaromatichydrocarbon. Thus, the term collectively includes alkyl, alkenyl andalkynyl groups.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” as usedherein, alone or in combination, refer to optionally substituted alkyl,alkenyl and alkynyl structures respectively, as described above, inwhich one or more of the skeletal chain carbon atoms (and any associatedhydrogen atoms, as appropriate) are each independently replaced with aheteroatom (i.e. an atom other than carbon, such as though not limitedto oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinationsthereof), or heteroatomic group such as though not limited to —O—O—,—S—S—, —O—S—, —S—O—, ═N—N═, —N═N—, —N═N—NH—, —P(O)₂—, —O—P(O)₂—,—P(O)₂—O—, —S(O)—, —S(O)₂—, —SnH₂— and the like.

The terms “haloalkyl”, “haloalkenyl” and “haloalkynyl” as used herein,alone or in combination, refer to optionally substituted alkyl, alkenyland alkynyl groups respectively, as defined above, in which one or morehydrogen atoms is replaced by fluorine, chlorine, bromine or iodineatoms, or combinations thereof. In some embodiments, two or morehydrogen atoms are replaced with halogen atoms that are the same as eachanother (e.g. difluoromethyl); in other embodiments, two or morehydrogen atoms are replaced with halogen atoms that are not all the sameas each other (e.g. 1-chloro-1-fluoro-1-iodoethyl). Non-limitingexamples of haloalkyl groups are fluoromethyl and bromoethyl. Anon-limiting example of a haloalkenyl group is bromoethenyl. Anon-limiting example of a haloalkynyl group is chloroethynyl.

The term “perhalo” as used herein, alone or in combination, refers togroups in which all of the hydrogen atoms are replaced by fluorines,chlorines, bromines, iodines, or combinations thereof. Thus, as anon-limiting example, the term “perhaloalkyl” refers to an alkyl group,as defined herein, in which all of the H atoms have been replaced byfluorines, chlorines, bromines or iodines, or combinations thereof. Anon-limiting example of a perhaloalkyl group isbromo,chloro,fluoromethyl. A non-limiting example of a perhaloalkenylgroup is trichloroethenyl. A non-limiting example of a perhaloalkynylgroup is tribromopropynyl.

The term “carbon chain” as used herein, alone or in combination, refersto any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl orheteroalkynyl group, which is linear, cyclic, or any combinationthereof. If the chain is part of a linker and that linker comprises oneor more rings as part of the core backbone, for purposes of calculatingchain length, the “chain” only includes those carbon atoms that composethe bottom or top of a given ring and not both, and where the top andbottom of the ring(s) are not equivalent in length, the shorter distanceshall be used in determining the chain length. If the chain containsheteroatoms as part of the backbone, those atoms are not calculated aspart of the carbon chain length.

The terms “cycle”, “cyclic”, “ring” and “membered ring” as used herein,alone or in combination, refer to any covalently closed structure,including alicyclic, heterocyclic, aromatic, heteroaromatic andpolycyclic fused or non-fused ring systems as described herein. In someembodiments, rings are optionally substituted. In some embodiments,rings form part of a fused ring system. The term “membered” is meant todenote the number of skeletal atoms that constitute the ring. Thus, byway of example only, cyclohexane, pyridine, pyran and pyrimidine aresix-membered rings and cyclopentane, pyrrole, tetrahydrofuran andthiophene are five-membered rings.

The term “fused” as used herein, alone or in combination, refers tocyclic structures in which two or more rings share one or more bonds.

The term “cycloalkyl” as used herein, alone or in combination, refers toan optionally substituted, saturated, hydrocarbon monoradical ring,containing from three to about fifteen ring carbon atoms or from threeto about ten ring carbon atoms. In some embodiments, the compoundincludes additional, non-ring carbon atoms as substituents (e.g.methylcyclopropyl). Whenever it appears herein, a numerical range suchas “C₃-C₆ cycloalkyl” or “C₃₋₆ cycloalkyl”, means: in some embodiments,the cycloalkyl group consists of 3 carbon atoms (e.g., cyclopropyl); insome embodiments, 4 carbon atoms (e.g., cyclobutyl); in someembodiments, 5 carbon atoms (e.g., cyclopentyl); in some embodiments, 6carbon atoms (e.g., cyclohepty). The present definition also covers theoccurrence of the term “cycloalkyl” where no numerical range isdesignated. Further, the term includes fused, non-fused, bridged andspiro radicals. A fused cycloalkyl contains from two to four fused ringswhere the ring of attachment is a cycloalkyl ring, and the otherindividual rings are alicyclic, heterocyclic, aromatic, heteroaromaticor any combination thereof. Examples include, but are not limited tocyclopropyl, cyclopentyl, cyclohexyl, decalinyl, andbicyclo[2.2.1]heptyl and adamantyl ring systems. Illustrative examplesinclude, but are not limited to the following moieties:

and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an optionally substituted hydrocarbon non-aromatic, monoradical ring,having one or more carbon-carbon double-bonds and from three to abouttwenty ring carbon atoms, three to about twelve ring carbon atoms, orfrom three to about ten ring carbon atoms. The term includes fused,non-fused, bridged and spiro radicals. A fused cycloalkenyl containsfrom two to four fused rings where the ring of attachment is acycloalkenyl ring, and the other individual rings are alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof. Insome embodiments, fused ring systems are fused across a bond that is acarbon-carbon single bond or a carbon-carbon double bond. Examples ofcycloalkenyls include, but are not limited to cyclohexenyl,cyclopentadienyl and bicyclo[2.2.1]hept-2-ene ring systems. Illustrativeexamples include, but are not limited to the following moieties:

and the like.

The terms “alicyclyl” or “alicyclic” as used herein, alone or incombination, refer to an optionally substituted, saturated, partiallyunsaturated, or fully unsaturated nonaromatic hydrocarbon ring systemscontaining from three to about twenty ring carbon atoms, three to abouttwelve ring carbon atoms, or from three to about ten ring carbon atoms.Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.

The terms “non-aromatic heterocyclyl” and “heteroalicyclyl” as usedherein, alone or in combination, refer to optionally substituted,saturated, partially unsaturated, or fully unsaturated nonaromatic ringmonoradicals containing from three to about twenty ring atoms, where oneor more of the ring atoms are an atom other than carbon, independentlyselected from among oxygen, nitrogen, sulfur, phosphorous, silicon,selenium and tin but are not limited to these atoms. Where two or moreheteroatoms are present in the ring, in some embodiments, the two ormore heteroatoms are the same as each another; in some embodiments, someor all of the two or more heteroatoms are different from the others. Theterms include fused, non-fused, bridged and spiro radicals. A fusednon-aromatic heterocyclic radical contains from two to four fused ringswhere the attaching ring is a non-aromatic heterocycle, and the otherindividual rings are alicyclic, heterocyclic, aromatic, heteroaromaticor any combination thereof. Fused ring systems are fused across a singlebond or a double bond, as well as across bonds that are carbon-carbon,carbon-hetero atom or hetero atom-hetero atom. The terms also includeradicals having from three to about twelve skeletal ring atoms, as wellas those having from three to about ten skeletal ring atoms. In someembodiments, attachment of a non-aromatic heterocyclic subunit to itsparent molecule is via a heteroatom; in some embodiments, via a carbonatom. In some embodiments, additional substitution is via a heteroatomor a carbon atom. As a non-limiting example, an imidazolidinenon-aromatic heterocycle is attached to a parent molecule via either ofits N atoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of itscarbon atoms (imidazolidin-2-yl, imidazolidin-4-yl orimidazolidin-5-yl). In certain embodiments, non-aromatic heterocyclescontain one or more carbonyl or thiocarbonyl groups such as, forexample, oxo- and thio-containing groups. Examples include, but are notlimited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include:

and the like. The terms also include all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “aromatic” as used herein, refers to a planar, cyclic orpolycyclic, ring moiety having a delocalized π-electron systemcontaining 4n+2 π electrons, where n is an integer. In some embodiments,aromatic rings are formed by five atoms; in some embodiments, six atoms;in some embodiments, seven atoms; in some embodiments, eight atoms; insome embodiments, nine atoms; in some embodiments, more than nine atoms.Aromatics are optionally substituted and are monocyclic or fused-ringpolycyclic. The term aromatic encompasses both all carbon containingrings (e.g., phenyl) and those rings containing one or more heteroatoms(e.g., pyridine).

The term “aryl” as used herein, alone or in combination, refers to anoptionally substituted aromatic hydrocarbon radical of six to abouttwenty ring carbon atoms, and includes fused and non-fused aryl rings. Afused aryl ring radical contains from two to four fused rings, where thering of attachment is an aryl ring, and the other individual rings arealicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Further, the term aryl includes fused and non-fused ringscontaining from six to about twelve ring carbon atoms, as well as thosecontaining from six to about ten ring carbon atoms. A non-limitingexample of a single ring aryl group includes phenyl; a fused ring arylgroup includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and anon-fused bi-aryl group includes biphenyl.

The term “arylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, aryl. Examplesinclude, but are not limited to 1, 2-phenylene, 1,3-phenylene,1,4-phenylene, 1,2-naphthylene and the like.

The term “heteroaryl” as used herein, alone or in combination, refers tooptionally substituted aromatic monoradicals containing from about fiveto about twenty skeletal ring atoms, where one or more of the ring atomsis a heteroatom independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but not limited to theseatoms and with the proviso that the ring of the group does not containtwo adjacent O or S atoms. Where two or more heteroatoms are present inthe ring, in some embodiments, the two or more heteroatoms are the sameas each another; in some embodiments, some or all of the two or moreheteroatoms are be different from the others. The term heteroarylincludes optionally substituted fused and non-fused heteroaryl radicalshaving at least one heteroatom. The term heteroaryl also includes fusedand non-fused heteroaryls having from five to about twelve skeletal ringatoms, as well as those having from five to about ten skeletal ringatoms. In some embodiments, bonding to a heteroaryl group is via acarbon atom; in some embodiments, via a heteroatom. Thus, as anon-limiting example, an imidiazole group is attached to a parentmolecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl orimidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl).Further, in some embodiments, a heteroaryl group is substituted via anyor all of its carbon atoms, and/or any or all of its heteroatoms. Afused heteroaryl radical contains from two to four fused rings, wherethe ring of attachment is a heteroaromatic ring. In some embodiments,the other individual rings are alicyclic, heterocyclic, aromatic,heteroaromatic or any combination thereof. A non-limiting example of asingle ring heteroaryl group includes pyridyl; fused ring heteroarylgroups include benzimidazolyl, quinolinyl, acridinyl; and a non-fusedbi-heteroaryl group includes bipyridinyl. Further examples ofheteroaryls include, without limitation, furanyl, thienyl, oxazolyl,acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl,benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl,indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl,pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl,purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl,quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyland the like, and their oxides, such as for example pyridyl-N-oxide.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

The term “heteroarylene” as used herein, alone or in combination, refersto a diradical derived from the above-defined monoradical heteroaryl.Examples include, but are not limited to pyridinyl and pyrimidinyl.

The term “heterocyclyl” as used herein, alone or in combination, referscollectively to heteroalicyclyl and heteroaryl groups. Herein, wheneverthe number of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one non-carbon atom (the heteroatom) must bepresent in the ring. Designations such as “C₁-C₆ heterocycle” refer onlyto the number of carbon atoms in the ring and do not refer to the totalnumber of atoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Forheterocycles having two or more heteroatoms, in some embodiments, thosetwo or more heteroatoms are the same; in some embodiments, they aredifferent from one another. In some embodiments, heterocycles aresubstituted. Non-aromatic heterocyclic groups include groups having onlythree atoms in the ring, while aromatic heterocyclic groups must have atleast five atoms in the ring. In some embodiments, bonding (i.e.attachment to a parent molecule or further substitution) to aheterocycle is via a heteroatom; in some embodiments, via a carbon atom.

The term “carbocyclyl” as used herein, alone or in combination, referscollectively to alicyclyl and aryl groups; i.e. all carbon, covalentlyclosed ring structures. In some embodiments, the carbocyclyl issaturated, partially unsaturated, fully unsaturated or aromatic. In someembodiments, carbocyclic rings are formed by three, carbon atoms; insome embodiments, four carbon atoms; in some embodiments, five carbonatoms; in some embodiments, six carbon atoms; in some embodiment, sevencarbon atoms; in some embodiments, eight carbon atoms; in someembodiments, nine carbon atoms; in some embodiments, more than ninecarbon atoms. Carbocycles are optionally substituted. The termdistinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.

The terms “halogen”, “halo” or “halide” as used herein, alone or incombination refer to fluoro, chloro, bromo and iodo.

The term “hydroxy” as used herein, alone or in combination, refers tothe monoradical —OH.

The term “cyano” as used herein, alone or in combination, refers to themonoradical —CN.

The term “cyanomethyl” as used herein, alone or in combination, refersto the monoradical —CH₂CN.

The term “nitro” as used herein, alone or in combination, refers to themonoradical —NO₂.

The term “oxy” as used herein, alone or in combination, refers to thediradical —O—.

The term “oxo” as used herein, alone or in combination, refers to thediradical ═O.

The term “carbonyl” as used herein, alone or in combination, refers tothe diradical —C(═O)—, which is also written as —C(O)—.

The terms “carboxy” or “carboxyl” as used herein, alone or incombination, refer to the moiety —C(O)OH, which is alternatively writtenas —COOH.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, —O-alkyl, including the groups —O-aliphatic and—O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups areoptionally substituted, and wherein the terms alkyl, aliphatic andcarbocyclyl are as defined herein. Non-limiting examples of alkoxyradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “sulfinyl” as used herein, alone or in combination, refers tothe diradical —S(═O)—.

The term “sulfonyl” as used herein, alone or in combination, refers tothe diradical —S(═O)₂—.

The terms “sulfonamide”, “sulfonamido” and “sulfonamidyl” as usedherein, alone or in combination, refer to the diradical groups—S(═O)₂—NH— and —NH—S(═O)₂—.

The terms “sulfamide”, “sulfamido” and “sulfamidyl” as used herein,alone or in combination, refer to the diradical group —NH—S(═O)₂—NH—.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

Certain Pharmaceutical Terminology

The term “subject”, “patient” or “individual” as used herein inreference to individuals suffering from a disease, and encompassesmammals and non-mammals. Mammals are any member of the Mammalian class,including but not limited to humans, non-human primates such aschimpanzees, and other apes and monkey species; farm animals such ascattle, horses, sheep, goats, swine; domestic animals such as rabbits,dogs, and cats; laboratory animals including rodents, such as rats, miceand guinea pigs, and the like. Examples of non-mammals include, but arenot limited to, birds, fish and the like. In some embodiments of themethods and compositions provided herein, the subject is a mammal. Inpreferred embodiments, the subject is a human. None of the terms shouldbe construed as requiring the supervision od a medical profesisonal(e.g., a physician, nurse, physician's assistant, orderly, hospiceworker, etc.).

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition symptoms, preventing additional symptoms,ameliorating or preventing the underlying metabolic causes of symptoms,inhibiting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused bythe disease or condition, or stopping the symptoms of the disease orcondition, and are intended to include prophylaxis. The terms furtherinclude achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disease being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disease such thatan improvement is observed in the patient, notwithstanding that, in someembodiments, the patient is still afflicted with the underlying disease.For prophylactic benefit, the compositions are administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even if adiagnosis of the disease has not been made.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that are used to enable delivery ofcompounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. In some embodiments, the result is areduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in a disease. In someembodiments, the “effective” amount differs from one individual toanother. In some embodiments, an appropriate “effective” amount isdetermined using any suitable technique (e.g., a dose escalation study).

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the subject being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of a compound disclosed herein, and isrelatively nontoxic (i.e., when the material is administered to anindividual it does not cause undesirable biological effects nor does itinteract in a deleterious manner with any of the components of thecomposition in which it is contained).

The term “prodrug” as used herein, refers to a drug precursor that,following administration to a subject and subsequent absorption, isconverted to an active, or a more active species via some process, suchas conversion by a metabolic pathway. Thus, the term encompasses anyderivative of a compound, which, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or a pharmaceutically active metabolite or residue thereof.Some prodrugs have a chemical group present on the prodrug that rendersit less active and/or confers solubility or some other property to thedrug. Once the chemical group has been cleaved and/or modified from theprodrug the active drug is generated. Particularly favored derivativesor prodrugs are those that increase the bioavailability of the compoundsof this invention when such compounds are administered to a patient(e.g. by allowing an orally administered compound to be more readilyabsorbed into the blood) or which enhance delivery of the parentcompound to a biological compartment (e.g. the brain or lymphaticsystem).

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of the specified compound and that are not biologically orotherwise undesirable. In some embodiments, a compound disclosed hereinpossess acidic or basic groups and therefore react with any of a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed.

The term “pharmaceutical composition,” as used herein, refers to abiologically active compound, optionally mixed with at least onepharmaceutically acceptable chemical component, such as, though notlimited to carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, excipients and the like.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “pharmaceutical combination”, “administering an additionaltherapy”, “administering an additional therapeutic agent” and the like,as used herein, refer to a pharmaceutical therapy resulting from themixing or combining of more than one active ingredient and includes bothfixed and non-fixed combinations of a compound or composition disclosedherein. The term “fixed combination” means that at least one of acompound disclosed herein, and at least one co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that at least one of acompound disclosed herein, and at least one co-agent, are administeredto a patient as separate entities either simultaneously, concurrently orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

The terms “co-administration”, “administered in combination with” andtheir grammatical equivalents or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments, a compounddisclosed herein will be co-administered with other agents. These termsencompass administration of two or more agents to an animal so that bothagents and/or their metabolites are present in the animal at the sametime. They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments, the compounds of the invention and the otheragent(s) are administered in a single composition. In some embodiments,compounds of the invention and the other agent(s) are admixed in thecomposition.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. In some embodiments, enzymes produce structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism is found in The Pharmacological Basis of Therapeutics, 9thEdition, McGraw-Hill (1996).

Compounds

Disclosed herein, in certain embodiments, is a compound of formula (I):

wherein

-   -   X is O or S;    -   L is —(CR^(x)R^(x′))_(x)—(CR^(y)R^(y′))_(y)—(CR^(z)R^(z′))_(z)—;        wherein    -   x is 0 or 1;    -   y is 0 or 1;    -   z is 0 or 1;    -   R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each        independently H, F, Cl, Br, I or optionally substituted C₁₋₃        alkyl; or    -   R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), or        R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together        with the carbon atoms to which they are attached, form an        optionally substituted, aromatic or non-aromatic, 3-7 membered        ring, optionally comprising 1 or 2 heteroatoms selected from O,        N and S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   R^(A) is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted n-propyl, optionally substituted        i-propyl, CF₃, CHF₂ or CH₂F;    -   R^(B) is

-   -   a is 0, 1 or 2;    -   R^(1a) is H or optionally substituted C₁₋₃ alkyl;    -   R^(1a′) is H or optionally substituted C₁₋₃ alkyl; or    -   R^(1a) and R^(1a′) together with the carbon atom to which they        are attached form an optionally substituted 3-, 4-, 5- or        6-membered ring, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   R^(1b), R^(1c), R^(1d), R^(1e) and R^(1f) are each independently        H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″        aryl, heterocyclyl or heteroaryl; or    -   R^(1b) and R^(1c), or R^(1c) and R^(1d), or R^(1d) and R^(1e),        or R^(1e) and R^(1f) together with the two carbon atoms to which        they are attached, form an optionally substituted, aromatic or        non-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1        or 2 heteroatoms selected from O, N and S, and wherein said ring        may be optionally fused to 1 or 2 additional optionally        substituted, aromatic or non-aromatic, 5-, 6- or 7-membered        rings, optionally comprising 1 or 2 heteroatoms selected from O,        N and S; and wherein the optional substituents are each        independently H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,        cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′,        CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring;    -   R^(C) is an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, OR^(2a), SR^(3a), NR^(4a)R^(4b), or a        combination thereof, wherein;    -   R^(2a) is substituted C₁-C₄ alkyl, optionally substituted C₅-C₁₀        alkyl, optionally substituted heteroalkyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl or optionally substituted        heteroaryl; or    -   R^(2a) is a pharmaceutically acceptable cation; or    -   R^(2a) is —[C(R^(5a))(R^(5b))]_(m)R^(5c);    -   R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl,        optionally substituted heteroalkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl; or    -   R^(3a) is —[C(R^(5a))(R^(5b))]_(n)R^(5c);    -   R^(4a) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; and    -   R^(4b) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; or    -   R^(4b) is —[C(R^(5a))(R^(5b))]_(n)R^(5c), wherein    -   R^(5a) and R^(5b) are each independently hydrogen, halogen,        cyano, nitro, an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃        alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally        substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅        alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally        substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇        cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,        optionally substituted -L-C₁-C₄ haloalkyl, optionally        substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄        alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine,        optionally substituted -L-C₅-C₇ aryl, optionally substituted        -L-C₅-C₇ heteroaryl,

-   -   R^(5c) is hydrogen, halogen, cyano, nitro, an amino acid, a        dipeptide, a tripeptide, a tetrapeptide, a polypeptide, a lipid,        a phospholipid, a glycoside, a nucleoside, a nucleotide, an        oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,        substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉        alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally        substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅        heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl,        optionally substituted L-C₃-C₇ cycloalkenyl, optionally        substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted        -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy,        optionally substituted -L-C₁-C₄alkylamine, optionally        substituted -L-di(C₁-C₄)alkylamine, optionally substituted        -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂;

-   -   y₁ is 0, 1, 2 or 3;    -   Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂,        OP(O)(OH)₂, OP(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein    -   Y² and Y³ are each independently hydrogen or methyl; or    -   Y² and Y³ are taken together with the nitrogen to which they are        attached form a five or six membered ring that optionally        contains an oxygen atom or a second nitrogen atom; and    -   Y⁴ is an electron pair or an oxygen atom;    -   m is 1, 2, 3, 4;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;        or a metabolite, pharmaceutically acceptable salt, solvate,        ester, tautomer or prodrug thereof

In some embodiments, X is O. In some embodiments, X is S.

In some embodiments, x is 1, y is 0 and z is 0.

In some embodiments, X is S, x is 1, y is 0 and z is 0.

In some embodiments, R^(x) and R^(x′) are H, F or methyl. In someembodiments, R^(x) and R^(x′) are both H. In some embodiments, R^(x) andR^(x′) are both F. In some embodiments, R^(x) and R^(x′) are bothmethyl.

In some embodiments, x is 1, y is 0, z is 0, R^(x) is H and R^(x′) is H.

In some embodiments, x is 1, y is 0, z is 0, R^(x) is F and R^(x′) is F.

In some embodiments, x is 1, y is 0, z is 0, R^(x) is methyl and R^(x′)is methyl.

In some embodiments, X is S, x is 1, y is 0, z is 0 and R^(x) and R^(x′)are either both H or both F.

In some embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) andR^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring,optionally comprising 1 or 2 heteroatoms selected from O, N and S, andwherein said ring may be optionally fused to 1 or 2 additionaloptionally substituted, aromatic or non-aromatic, 5-, 6- or 7-memberedrings, optionally comprising 1 or 2 heteroatoms selected from O, N andS. In some embodiments, R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z)and R^(z′), or R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring. Insome embodiments, R^(x) and R^(x′) together with the carbon atoms towhich they are attached, form an optionally substituted, aromatic ornon-aromatic, 3-7 membered ring. In some embodiments, R^(x) and R^(y)together with the carbon atoms to which they are attached, form anoptionally substituted, aromatic or non-aromatic, 3-7 membered ring.

In some embodiments, R^(A) is H. In some embodiments, R^(A) is Br.

In some embodiments, a is 0.

In some embodiments, R^(1b), R^(1c), R^(1d), R^(1e) and R^(1f) are eachindependently H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,COOR′, CONH₂, CONHR′, CONR′R″SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′,S(O)₂NR′R″ aryl, heterocyclyl or heteroaryl.

In some embodiments, R^(1b) and R^(1c), or R^(1c) and R^(1d), or R^(1d)and R^(1e), or R^(1e) and R^(1f) together with the two carbon atoms towhich they are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S. In some embodiments, R^(1b) andR^(1c) together with the two carbon atoms to which they are attached,form an optionally substituted, aromatic or non-aromatic, 5-, 6- or7-membered ring. In some embodiments, R^(1b) and R^(1c) together withthe two carbon atoms to which they are attached, form an optionallysubstituted, aromatic 5-, 6- or 7-membered ring. In some embodiments,R^(1b) and R^(1c) together with the two carbon atoms to which they areattached, form an optionally substituted, aromatic 6-membered ring.

In some embodiments, R^(B) is

wherein

-   -   R^(1g) is H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,        cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′,        CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring.

In some embodiments, R^(B) is

In some embodiments, R^(1e), R^(1f) and R^(1g) are H.

In some embodiments, R^(1d) is CN, alkyl or cycloalkyl.

In some embodiments, R^(1e), R^(1f) and R^(1g) are H and R^(1d) is CN,alkyl or cycloalkyl. In some embodiments, R^(1e), R^(1f) and R^(1g) areH and R^(1d) is CN or cyclopropyl.

In some embodiments, R^(B) is

In some embodiments, X is S, x is 1, y is 0, z is 0 and R^(x) and R^(x′)are either both H or both F.

In some embodiments, R^(C) is an amino acid, a dipeptide, a tripeptide.In some embodiments, R^(C) is an amino acid or a dipeptide. In someembodiments, R^(C) is glycine, alanine or valine. In some embodiments,R^(C) is a dipeptide comprising glycine, alanine or valine.

Disclosed herein, in certain embodiments, is a compound of Formula(I-A):

wherein

-   -   X is O or S;    -   R^(A) is H, Cl, Br, I, NH₂, methyl, ethyl, n-propyl, i-propyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted n-propyl, optionally substituted        i-propyl, CF₃, CHF₂ or CH₂F;    -   R^(1b), R^(1c), R^(1d), R^(1e) and R^(1f) are each independently        H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″        aryl, heterocyclyl or heteroaryl; or    -   R^(1b) and R^(1c), or R^(1c) and R^(1d), or R^(1d) and R^(1e),        or R^(1e) and R^(1f) together with the two carbon atoms to which        they are attached, form an optionally substituted, aromatic or        non-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1        or 2 heteroatoms selected from O, N and S, and wherein said ring        may be optionally fused to 1 or 2 additional optionally        substituted, aromatic or non-aromatic, 5-, 6- or 7-membered        rings, optionally comprising 1 or 2 heteroatoms selected from O,        N and S; and wherein the optional substituents are each        independently H, F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,        cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′,        CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring;    -   R^(C) is an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, OR^(2a), SR^(3a), NR^(4a)R^(4b), or a        combination thereof, wherein;    -   R^(2a) is substituted hydrogen, optionally substituted C₁-C₁₀        alkyl, optionally substituted heteroalkyl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted aryl or optionally substituted        heteroaryl; or    -   R^(2a) is a pharmaceutically acceptable cation; or    -   R^(2a) is —[C(R^(5a))(R^(5b))]_(m)R^(5c);    -   R^(3a) is hydrogen, optionally substituted C₁-C₁₀ alkyl,        optionally substituted heteroalkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl; or    -   R^(3a) is —[C(R^(5a))(R^(5b))]_(n)R^(5c);    -   R^(4a) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; and    -   R^(4b) is hydrogen, optionally substituted alkyl, optionally        substituted heteroalkyl, optionally substituted cycloalkyl or        optionally substituted heterocycloalkyl; or    -   R^(4b) is —[C(R^(5a))(R^(5b))]_(n)R^(5c), wherein    -   R^(5a) and R^(5b) are each independently hydrogen, halogen,        cyano, nitro, an amino acid, a dipeptide, a tripeptide, a        tetrapeptide, a polypeptide, a lipid, a phospholipid, a        glycoside, a nucleoside, a nucleotide, an oligonucleotide,        polyethylene glycol, -L-OH, -L-SH, -L-NH₂, substituted -L-C₁-C₃        alkyl, optionally substituted -L-C₄-C₉ alkyl, optionally        substituted L-C₂-C₅ alkenyl, optionally substituted L-C₂-C₅        alkynyl, optionally substituted L-C₂-C₅ heteroalkyl, optionally        substituted -L-C₃-C₇ cycloalkyl, optionally substituted L-C₃-C₇        cycloalkenyl, optionally substituted -L-C₃-C₇ heterocycloalkyl,        optionally substituted -L-C₁-C₄ haloalkyl, optionally        substituted -L-C₁-C₄ alkoxy, optionally substituted -L-C₁-C₄        alkylamine, optionally substituted -L-di-(C₁-C₄)alkylamine,        optionally substituted -L-C₅-C₇ aryl, optionally substituted        -L-C₅-C₇ heteroaryl,

-   -   R^(5c) is hydrogen, halogen, cyano, nitro, an amino acid, a        dipeptide, a tripeptide, a tetrapeptide, a polypeptide, a lipid,        a phospholipid, a glycoside, a nucleoside, a nucleotide, an        oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH₂,        substituted -L-C₁-C₃ alkyl, optionally substituted -L-C₄-C₉        alkyl, optionally substituted L-C₂-C₅ alkenyl, optionally        substituted L-C₂-C₅ alkynyl, optionally substituted L-C₂-C₅        heteroalkyl, optionally substituted -L-C₃-C₇ cycloalkyl,        optionally substituted L-C₃-C₇ cycloalkenyl, optionally        substituted -L-C₃-C₇ heterocycloalkyl, optionally substituted        -L-C₁-C₄ haloalkyl, optionally substituted -L-C₁-C₄ alkoxy,        optionally substituted -L-C₁-C₄alkylamine, optionally        substituted -L-di(C₁-C₄)alkylamine, optionally substituted        -L-C₅-C₇ aryl, optionally substituted -L-C₅-C₇ heteroaryl,

wherein L is a bond, —C(O)—, —S(O), or —S(O)₂;

-   -   y₁ is 0, 1, 2 or 3;    -   Y is OH, OMe, COOH, SO₃H, OSO₃H, OS(O)₂NH₂, P(O)(OH)₂,        OP(O)(OH)₂, OP(O)(O)(OH)(O—C₁₋₄ alkyl) or NY²Y³Y⁴; wherein    -   Y² and Y³ are each independently hydrogen or methyl; or    -   Y² and Y³ are taken together with the nitrogen to which they are        attached form a five or six membered ring that optionally        contains an oxygen atom or a second nitrogen atom; and    -   Y⁴ is an electron pair or an oxygen atom;    -   m is 1, 2, 3, 4;    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;    -   R^(D) is a natural or unnatural amino acid residue;        or a metabolite, pharmaceutically acceptable salt, solvate,        ester, tautomer or prodrug thereof.

Disclosed herein are compounds of formula (II), or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof:

wherein:

-   -   W is O, S, S(O), S(O)₂, NH, N(optionally substituted alkyl),        CH₂, CH₂O, CH₂S or CH₂NH;    -   R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH, NO₂, NH₂,        NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃,        CO₂-alkyl, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkoxy, optionally substituted        S-alkyl, optionally substituted cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl or        optionally substituted heteroaryl;    -   a is 0, 1 or 2;    -   R^(a) is H or optionally substituted C₁₋₃ alkyl;    -   R^(a′) is H or optionally substituted C₁₋₃ alkyl; or    -   R^(a) and R^(a′) together with the carbon atom to which they are        attached form an optionally substituted, 3-, 4-, 5- or        6-membered ring, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   R^(b), R^(c), R^(d), R^(e) and R^(f) are each independently H,        F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,        aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring; or    -   R^(b) and R^(c), or R^(c) and R^(d), or R^(d) and R^(e), or        R^(e) and R^(f) together with the two carbon atoms to which they        are attached, form an optionally substituted, aromatic or        non-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1        or 2 heteroatoms selected from O, N and S, and wherein said ring        may be optionally fused to 1 or 2 additional optionally        substituted, aromatic or non-aromatic, 5-, 6- or 7-membered        rings, optionally comprising 1 or 2 heteroatoms selected from O,        N and S; and wherein the optional substituents are each        independently F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl,        cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′,        CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl;    -   x is 0 or 1;    -   y is 0 or 1;    -   z is 0 or 1;    -   R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each        independently H, F, Cl, Br, or optionally substituted C₁₋₃        alkyl; or    -   R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), or        R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together        with the carbon atoms to which they are attached, form an        optionally substituted, aromatic or non-aromatic, 3-7 membered        ring, optionally comprising 1 or 2 heteroatoms selected from O,        N and S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   A is H, C(O)O—B¹ or C(O)NH—B²; wherein    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation;    -   B² is H or optionally substituted C₁₋₆ alkyl; and wherein        all alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and        heteroaryl moieties may be optionally further substituted.

Another aspect of the invention provides for a compound of formula(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I)or (II-J), or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

wherein:

-   -   W is O, S, S(O), S(O)₂, NH, N(optionally substituted alkyl),        CH₂, CH₂O, CH₂S or CH₂NH;    -   R¹ is H, F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH, NO₂, NH₂,        NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃,        CO₂-alkyl, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkoxy, optionally substituted        S-alkyl, optionally substituted cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl or        optionally substituted heteroaryl;    -   a is 0, 1 or 2;    -   R^(a) is H or optionally substituted C₁₋₃ alkyl;    -   R^(a′) is H or optionally substituted C₁₋₃ alkyl; or    -   R^(a) and R^(a′) together with the carbon atom to which they are        attached form a 3-, 4-, 5- or 6-membered ring, optionally        comprising 1 or 2 heteroatoms selected from O, N and S;    -   R^(d), R^(e), R^(f), R^(g) and R^(h) are each independently H,        F, Cl, Br, I, CF₃, CN, alkyl, cycloalkyl, cyclopropylmethyl,        NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂,        CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,        aryl, heterocyclyl or heteroaryl;        wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring;    -   R³ is        —(CR^(x)R^(x′))_(x)—(CR^(y)R^(y′))_(y)—(CR^(z)R^(z′))_(z)-A;        wherein    -   x is 0 or 1;    -   y is 0 or 1;    -   z is 0 or 1;    -   R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′) are each        independently H, F, Cl, Br, or optionally substituted C₁₋₃        alkyl; or    -   R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), or        R^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together        with the carbon atoms to which they are attached, form an        optionally substituted, aromatic or non-aromatic, 3-7 membered        ring, optionally comprising 1 or 2 heteroatoms selected from O,        N and S, and wherein said ring may be optionally fused to 1 or 2        additional optionally substituted, aromatic or non-aromatic, 5-,        6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms        selected from O, N and S;    -   A is H, C(O)O—B¹ or C(O)NH—B²; wherein    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation;    -   B² is H or optionally substituted C₁₋₆ alkyl; and wherein        all alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and        heteroaryl moieties may be optionally further substituted.

Another aspect of the invention provides for a compound of formula(IIK), (IIL), (IIM), (IIN), (IIO) or (IIP), or a metabolite,pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof:

wherein:

-   -   R^(g) and R^(h) are each independently H, F, Cl, Br, I, CF₃, CN,        alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′,        SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or        heteroaryl; wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring.

In other embodiments, the invention provides compounds of formula(II-Q), or a metabolite, pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof:

wherein:

-   -   R^(i) and R^(j) are each independently H, F, Cl, Br, I, CF₃, CN,        alkyl, cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′,        SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or        heteroaryl; wherein    -   R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl;    -   R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ together with the nitrogen atom to which they are        attached form an optionally substituted, saturated or        unsaturated 4-, 5- or 6-membered heterocyclic ring.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is H, F, Cl, Br, I, —CH₂F, —CF₂H, —CF₃, —CN, —OH, —NO₂, —NH₂,        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —CO₂—C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,        C₁₋₄S-alkyl, C₃₋₆cycloalkyl, optionally substituted        C₁₋₆heterocycloalkyl, optionally substituted phenyl, or        optionally substituted 5 or 6 membered heteroaryl;    -   R^(d) is F, Cl, Br, I, CF₃, aryl, heteroaryl, CN, NO₂, NH₂,        NHR′, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′,        CONR′R″, SO₃H, SO₃R′, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or        S(O)₂NR′R″;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) and R^(x′) are each independently H, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted heteroalkyl,        optionally substituted heteroalkenyl, optionally substituted        heteroalkynyl, optionally substituted cycloalkyl, optionally        substituted cycloalkenyl, optionally substituted heterocyclyl,        optionally substituted aryl, optionally substituted heteroaryl,        halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,        COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, or S(O)₂NR′R″; or    -   R^(x) and R^(x′) together with the carbon atom to which they are        attached, form an optionally substituted non-aromatic 3-7        membered ring, optionally comprising 1 or 2 heteroatoms selected        from O, N and S;    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and        each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x′) areindependently H, F, CF₃, or methyl. In some embodiments, R^(x) is F andR^(x′) is F. In some embodiments, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, or CH₃. In some embodiments, R¹ is Br. In some embodiments, R^(d)is H, F, Cl, Br, I, CF₃, or CN.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is H, F, Cl, Br, I, —CH₂F, —CF₂H, —CF₃, —CN, —OH, —NO₂, —NH₂,        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —SO₂CH₃, —SO₂NH₂,        —SO₂NHCH₃, —CO₂—C₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkoxy,        C₁₋₄S-alkyl, C₃₋₆cycloalkyl, optionally substituted        C₁₋₆heterocycloalkyl, optionally substituted phenyl, or        optionally substituted 5 or 6 membered heteroaryl;    -   R^(d) is H, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NO₂, NH₂, NHR′, NR′R″, OH,        OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H,        SO₃R′, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) is F, Cl, Br, I, or C₁-C₃ fluoroalkyl;    -   R^(x′) is independently H, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted heteroalkyl, optionally substituted        heteroalkenyl, optionally substituted heteroalkynyl, optionally        substituted cycloalkyl, optionally substituted cycloalkenyl,        optionally substituted heterocyclyl, optionally substituted        aryl, optionally substituted heteroaryl, halo, CN, NH₂, NHR′,        NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′,        CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, or S(O)₂NR′R″; and    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and        each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x′) areindependently H, F, methyl, or CF₃. In some embodiments, R^(x) is F andR^(x1) is F. In some embodiments, R¹ is H, F, Cl, Br, CH₂F, CF₂H, CF₃,NH₂, or CH₃. In some embodiments, R¹ is Br. In some embodiments, R^(d)is F, Cl, Br, I, CF₃, or CN.

Disclosed herein, in certain embodiments, is a compound having thefollowing structure:

or a metabolite, pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof,wherein:

-   -   W is O or S;    -   R¹ is halo or haloalkyl;    -   R^(d) is H;    -   R^(d1) is zero to four substituents independently selected from        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted        heteroalkyl, optionally substituted heteroalkenyl, optionally        substituted heteroalkynyl, optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH,        SR′, C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′,        S(O)₂NH₂, S(O)2NHR′, or S(O)₂NR′R″;    -   each R′ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl;    -   each R″ is independently methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or    -   R′ and R″ are together with the atom to which they are attached        form an optionally substituted, saturated or unsaturated 4-, 5-        or 6-membered ring;    -   R^(x) and R^(x′) are each independently H, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted heteroalkyl,        optionally substituted heteroalkenyl, optionally substituted        heteroalkynyl, optionally substituted cycloalkyl, optionally        substituted cycloalkenyl, optionally substituted heterocyclyl,        optionally substituted aryl, optionally substituted heteroaryl,        halo, CN, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H,        COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,        S(O)₂NHR′, or S(O)₂NR′R″; or    -   R^(x) and R^(x′) together with the carbon atom to which they are        attached, form an optionally substituted non-aromatic 3-7        membered ring, optionally comprising 1 or 2 heteroatoms selected        from O, N and S;    -   B³ is OB¹, NB² ₂, or an amino acid residue or an alkyl ester        thereof;    -   B¹ is H, optionally substituted C₁₋₆ alkyl or a pharmaceutically        acceptable cation; and        each B² is independently H or optionally substituted alkyl.

In some embodiments, W is S. In some embodiments, W is O. In someembodiments, B³ is OB¹. In some embodiments, B¹ is an alkali earth metalcation or an alkaline earth metal cation. In some embodiments, B³ is NB²₂. The compound disclosed herein wherein B³ is an amino acid residue orlower alkyl ester thereof. In some embodiments, R^(x) and R^(x1) areindependently H, F, CF₃, or methyl. In some embodiments, R^(x) is methyland R^(x1) is methyl.

Synthetic Procedures

In another aspect, methods for synthesizing a compound disclosed hereinare provided. A compound disclosed herein is prepared by any of themethods described below. The procedures and examples below are intendedto illustrate those methods. Neither the procedures nor the examplesshould be construed as limiting the invention in any way. A compounddisclosed herein is also synthesized using standard synthetic techniquesor using such methods in combination with methods described herein.

In some embodiments, the starting materials used for the synthesis ofthe compounds as described herein are obtained from commercial sources,such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.). In some embodiments, the starting materials aresynthesized.

A compound disclosed herein, and other related compounds havingdifferent substituents is synthesized using any suitable technique, suchas described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4^(th)Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th)Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVEGROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999) (all of which areincorporated by reference for such disclosures). The various moietiesfound in the formulae as provided herein are obtained using any suitablemethod. The following synthetic methods serve as a guide forsynthesizing a compound disclosed herein.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

In some embodiments, a compound disclosed herein is modified usingvarious electrophiles or nucleophiles to form new functional groups orsubstituents. The table below entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected examples of covalent linkages andprecursor functional groups. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

Examples of Covalent Linkages and Precursors Thereof Covalent LinkageProduct Electrophile Nucleophile Carboxamides Activated estersAmines/anilines Carboxamides Acyl azides Amines/anilines CarboxamidesAcyl halides Amines/anilines Esters Acyl halides Alcohols/phenols EstersAcyl nitriles Alcohols/phenols Carboxamides Acyl nitrilesAmines/anilines Imines Aldehydes Amines/anilines Hydrazones Aldehydes orketones Hydrazines Oximes Aldehydes or ketones Hydroxylamines Alkylamines Alkyl halides Amines/anilines Esters Alkyl halides Carboxylicacids Thioethers Alkyl halides Thiols Ethers Alkyl halidesAlcohols/phenols Thioethers Alkyl sulfonates Thiols Esters Alkylsulfonates Carboxylic acids Ethers Alkyl sulfonates Alcohols/phenolsEsters Anhydrides Alcohols/phenols Carboxamides AnhydridesAmines/anilines Thiophenols Aryl halides Thiols Aryl amines Aryl halidesAmines Thioethers Aziridines Thiols Boronate esters Boronates GlycolsCarboxamides Carboxylic acids Amines/anilines Esters Carboxylic acidsAlcohols Hydrazines Hydrazides Carboxylic acids N-acylureas orAnhydrides Carbodiimides Carboxylic acids Esters Diazoalkanes Carboxylicacids Thioethers Epoxides Thiols Thioethers Haloacetamides ThiolsAmmotriazines Halotriazines Amines/anilines Triazinyl ethersHalotriazines Alcohols/phenols Amidines Imido esters Amines/anilinesUreas Isocyanates Amines/anilines Urethanes Isocyanates Alcohols/phenolsThioureas Isothiocyanates Amines/anilines Thioethers Maleimides ThiolsPhosphite esters Phosphoramidites Alcohols Silyl ethers Silyl halidesAlcohols Alkyl amines Sulfonate esters Amines/anilines ThioethersSulfonate esters Thiols Esters Sulfonate esters Carboxylic acids EthersSulfonate esters Alcohols Sulfonamides Sulfonyl halides Amines/anilinesSulfonate esters Sulfonyl halides Phenols/alcoholsUse of Protecting Groups

In some embodiments, it is necessary to protect reactive functionalgroups, for example hydroxy, amino, imino, thio or carboxy groups, wherethese are desired in the final product, to avoid their unwantedparticipation in the reactions. Protecting groups are used to block someor all reactive moieties and prevent such groups from participating inchemical reactions until the protective group is removed. It ispreferred that each protective group be removable by a different means.Protective groups that are cleaved under totally disparate reactionconditions fulfill the requirement of differential removal. In someembodiments, protective groups are removed by acid, base,hydrogenolysis, or combinations thereof. In some embodiments, groupssuch as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl areacid labile and are used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. In some embodiments, carboxylic acid and hydroxy reactivemoieties are blocked with base labile groups such as, but not limitedto, methyl, ethyl, and acetyl in the presence of amines blocked withacid labile groups such as t-butyl carbamate or with carbamates that areboth acid and base stable but hydrolytically removable.

In some embodiments, carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group. In some embodiments, amine groups capable of hydrogenbonding with acids are blocked with base labile groups such as Fmoc. Insome embodiments, carboxylic acid reactive moieties are protected byconversion to simple ester compounds as exemplified herein. In someembodiments, carboxylic acid reactive moieties are blocked withoxidatively-removable protective groups such as 2,4-dimethoxybenzyl,while co-existing amino groups are blocked with fluoride labile silylcarbamates.

In some embodiments, allyl blocking groups are used in the presence ofacid- and base-protecting groups since the former are stable. In someembodiments, allyl blocking groups are subsequently removed by metal orpi-acid catalysts. For example, an allyl-blocked carboxylic acid isdeprotected with a Pd-catalyzed reaction in the presence of acid labilet-butyl carbamate or base-labile acetate amine protecting groups.

In some embodiments, the protecting group is a resin to which a compoundor intermediate is attached. In certain instances, as long as theresidue is attached to the resin, the functional group is blocked andcannot react. Once released from the resin, the functional group isavailable to react.

In some embodiments, the protecting group is:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosures.

Further Forms

Isomers

In some embodiments, a compound disclosed herein exists as geometricisomers. In some embodiments, a compound disclosed herein possesses oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof.

In some embodiments, compounds disclosed herein exist as tautomers. Acompound disclosed herein includes all possible tautomers within theformulas described herein. In some embodiments, a compound disclosedherein possesses one or more chiral centers. In some embodiments, eachcenter exists in the R or S configuration. A compound disclosed hereinincludes all diastereomeric, enantiomeric, and epimeric forms as well asthe corresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion are useful for the applications described herein.

In some embodiments, a compound disclosed herein is prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. In some embodiments, resolution ofenantiomers is carried out using covalent diastereomeric derivatives ofa compound disclosed herein. In some embodiments, resolution ofenantiomers is carried out using dissociable complexes (e.g.,crystalline diastereomeric salts). In certain instances, diastereomershave distinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.). In some embodiments, diastereomers areseparated by taking advantage of these dissimilarities. In someembodiments, diastereomers are separated by chiral chromatography, orpreferably, by separation/resolution techniques based upon differencesin solubility. The optically pure enantiomer is then recovered, alongwith the resolving agent, by any practical means that would not resultin racemization.

Labeled Compounds

In some embodiments, a compound disclosed herein exists in itsisotopically-labeled forms. The invention provides for methods oftreating diseases by administering such isotopically-labeled compounds.The invention further provides for methods of treating diseases byadministering such isotopically-labeled compounds as pharmaceuticalcompositions. Thus, compounds of formula I also includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Isotopes for use with a method orcompound disclosed herein include, but are not limited to, includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. A compound disclosed herein, andthe metabolites, pharmaceutically acceptable salts, esters, prodrugs,solvate, hydrates or derivatives thereof which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labeled compounds, forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.In some embodiments, substitution with heavy isotopes (e.g., deuterium,i.e., ²H) is utilized with a method or compound disclosed herein. Incertain instances, substitution with heavy isotopes affords certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. Insome embodiments, a compound, pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof is isotopically labeledby substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent in any procedure disclosed herein.

In some embodiments, a compound described herein is labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Metabolites

In some embodiments, a compound disclosed herein exists as a metabolite.The invention provides for methods of treating diseases by administeringsuch metabolites. The invention further provides for methods of treatingdiseases by administering such metabolites as pharmaceuticalcompositions.

In some embodiments, a compound disclosed herein is metabolized by avariety of metabolic mechanisms, such as hydrolysis, oxidation,glycolysis, phosphorylation, alkylation, dehalogenation, or combinationsthereof.

Pharmaceutically Acceptable Salts

In some embodiments, a compound disclosed herein exists as apharmaceutically acceptable salt. The invention provides for methods oftreating diseases by administering such pharmaceutically acceptablesalts. The invention further provides for methods of treating diseasesby administering such pharmaceutically acceptable salts aspharmaceutical compositions.

In some embodiments, a compound disclosed herein possesses an acidic orbasic group. In some embodiments, a compound disclosed herein thatpossesses an acidic or basic group reacts with any of a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, a salt isprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of a compound disclosed herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate. metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate.

Further, a compound disclosed herein is optionally prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, are optionally employedin the preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

In some embodiments, a compound disclosed herein which comprises a freeacid group reacts with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary or tertiary amine. Representative alkali or alkalineearth salts include the lithium, sodium, potassium, calcium, magnesium,and aluminum salts and the like. Illustrative examples of bases includesodium hydroxide, potassium hydroxide, choline hydroxide, sodiumcarbonate, N⁺(C₁₋₄ alkyl)₄, and the like. Representative organic aminesuseful for the formation of base addition salts include ethylamine,diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazineand the like. It should be understood that a compound disclosed hereinalso includes the quaternization of any basic nitrogen-containing groupsthey contain. In some embodiments, water or oil-soluble or dispersibleproducts are obtained by such quaternization. A compound disclosedherein is optionally prepared as pharmaceutically acceptable saltsformed when an acidic proton present in the parent compound either isreplaced by a metal ion, for example an alkali metal ion, an alkalineearth ion, or an aluminum ion; or coordinates with an organic base. Insome embodiments, base addition salts are also prepared by reacting thefree acid form of a compound disclosed herein with a pharmaceuticallyacceptable inorganic or organic base, including, but not limited toorganic bases such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like and inorganic bases suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like. In addition, the salt formsof the disclosed compounds are optionally prepared using salts of thestarting materials or intermediates.

Solvates

In some embodiments, a compound disclosed herein exists as a solvate.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

In certain instances, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent. In some embodiments, a solvateis formed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. In some embodiments, a solvate of a compounddisclosed herein is prepared or formed during the processes describedherein. By way of example only, hydrates of a compound disclosed hereinare conveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents including, but not limited to,dioxane, tetrahydrofuran or methanol. In some embodiments, a compoundprovided herein exists in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

Polymorphs

In some embodiments, a compound disclosed herein exists as a polymorph.The invention provides for methods of treating diseases by administeringsuch polymorphs. The invention further provides for methods of treatingdiseases by administering such polymorphs as pharmaceuticalcompositions.

Thus, a compound disclosed herein includes all crystalline forms, knownas polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. In certaininstances, polymorphs have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. In certaininstances, varying the recrystallization solvent, rate ofcrystallization, storage temperature, or a combination thereof resultsin a single crystal form dominating.

Prodrugs

In some embodiments, a compound disclosed herein exists as a prodrug.The invention provides for methods of treating diseases by administeringsuch prodrugs. The invention further provides for methods of treatingdiseases by administering such prodrugs as pharmaceutical compositions.

As used herein, a “prodrugs” is a drug precursor that, followingadministration to a subject and subsequent absorption, is converted toan active, or a more active species via some process, such as conversionby a metabolic pathway. Some prodrugs have a chemical group present onthe prodrug that renders it less active and/or confers solubility orsome other property to the drug. Once the chemical group has beencleaved and/or modified from the prodrug the active drug is generated.

In certain instances, prodrugs are useful as they easier to administerthan the parent drug. In certain instances, a prodrug is bioavailable byoral administration whereas the parent is not. In some embodiments, aprodrug has improved solubility in pharmaceutical compositions over theparent drug. An example, without limitation, of a prodrug would be acompound as described herein which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug is a short peptide (polyamino acid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety.

Various forms of prodrugs include those found, for example in Bundgaard,“Design and Application of Prodrugs” in A Textbook of Drug Design andDevelopment, Krosgaard-Larsen and Bundgaard, Ed., 1991, Chapter 5,113-191, which is incorporated herein by reference for such disclosures.

In some embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. The design of prodrugs to date has been toincrease the effective water solubility of the therapeutic compound fortargeting to regions where water is the principal solvent.

Additionally, prodrug derivatives of a compound disclosed herein areprepared by methods such as those described in Saulnier et al.,Bioorganic and Medicinal Chemistry Letters, 1994, 4, 1985). By way ofexample only, appropriate prodrugs are prepared by reacting anon-derivatized compound with a suitable carbamylating agent, such as,but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenylcarbonate, or the like. Prodrug forms of a compound disclosed herein,wherein the prodrug is metabolized in vivo to produce a derivative asset forth herein, are included within the scope of the claims. In someembodiments, some of the herein-described compounds are prodrugs foranother derivative or active compound.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e.g., two, three or four)nucleic acid residues is covalently joined to a compound of the presentinvention.

Pharmaceutically acceptable prodrugs of a compound disclosed herein alsoinclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters. In someembodiments, compounds having free amino, amido, hydroxy or carboxylicgroups are converted into prodrugs. For instance, free carboxyl groupsare derivatized as amides or alkyl esters. In some embodiments, aprodrug moiety incorporates groups including but not limited to ether,amine and carboxylic acid functionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters and disulfide containingesters; ethers, amides, carbamates, hemisuccinates,dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions. In some embodiments,incorporation of appropriate substituents on the aromatic ringstructures reduces, minimizes or eliminates this metabolic pathway.

Pharmacokinetics

In some embodiments, a compound described herein has an in vivo halflife of about 2 hours to about 10 hours. In some embodiments, a compounddescribed herein has an in vivo half life of about 2 hours to about 9hours. In some embodiments, a compound described herein has an in vivohalf life of about 2 hours to about 8 hours. In some embodiments, acompound described herein has an in vivo half life of about 2 hours toabout 7 hours. In some embodiments, a compound described herein has anin vivo half life of about 2 hours to about 6 hours. In someembodiments, a compound described herein has an in vivo half life ofabout 2 hours to about 5 hours. In some embodiments, a compounddescribed herein has an in vivo half life of about 2 hours to about 4hours. In some embodiments, a compound described herein has an in vivohalf life of about 2 hours to about 3 hours.

In some embodiments, a compound described herein has an in vivo halflife of about 2 hours, about 3 hours, about 4 hours, about 5 hours,about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10hours, about 12 hours, about 24 hours, about 2 days, about 3 days, about4 days, about 5 days, about 6 days, or about 7 days.

In some embodiments, a compound disclosed herein has an in vivo halflife of about 2.1 hours, about 2.2 hours, about 2.3 hours, about 2.4hours, about 2.5 hours, about 2.6 hours, about 2.7 hours, about 2.8hours, about 2.9 hours, about 3.1 hours, about 3.2 hours, about 3.3hours, about 3.4 hours, about 3.5 hours, about 3.6 hours, about 3.7hours, about 3.8 hours, about 3.9 hours.

Pharmaceutical Compositions

Described herein are pharmaceutical compositions. Further describedherein are uses of a compound disclosed herein in the preparation ofmedicaments for the treatment of disorders related to aberrant uric acidlevels in a tissue. In some embodiments, the pharmaceutical compositionscomprise an effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof. In some embodiments, thepharmaceutical compositions comprise an effective amount of a compounddisclosed herein, or a metabolite, pharmaceutically acceptable salt,ester, prodrug, solvate, hydrate or derivative thereof and at least onepharmaceutically acceptable carrier.

In some embodiments the pharmaceutical compositions are for thetreatment of a disease disclosed herein.

In some embodiments the pharmaceutical compositions are for thetreatment of diseases in a mammal. In some embodiments thepharmaceutical compositions are for the treatment of diseases in ahuman.

Formulations

A compound or composition described herein is administered either aloneor in combination with pharmaceutically acceptable carriers, excipientsor diluents, in a pharmaceutical composition, according to standardpharmaceutical practice. Administration of a compound or compositiondescribed herein is effected by any method that enables delivery of thecompounds to the site of action. These methods include, though are notlimited to delivery via enteral routes (including oral, gastric orduodenal feeding tube, rectal suppository and rectal enema), parenteralroutes (injection or infusion, including intraarterial, intracardiac,intradermal, intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration. In someembodiments, the most suitable route depends upon the condition anddisease of the recipient. By way of example only, a compound disclosedherein is administered locally to the area in need of treatment by localinfusion during surgery, topical application (e.g., as a cream orointment), injection (e.g., directly into the site of a diseased tissueor organ), catheter, or implant.

In some embodiments, a formulation suitable for oral administration ispresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of a compound or composition disclosedherein; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, acompound or composition disclosed herein is presented as a bolus,electuary or paste.

Pharmaceutical preparations for oral administration include tablets,solutions, suspension, push-fit capsules made of gelatin, as well assoft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In some embodiments, dye or pigment is added to anoral dosage form for identification or to characterize different doses.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,a compressed tablet is prepared by compressing in a suitable machine acompound or composition disclosed herein in a free-flowing form such asa powder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. In some embodiments, amolded tablet is made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. In someembodiments, a tablet disclosed herein is coated or scored. In someembodiments, a tablet disclosed herein is formulated so as to provideslow or controlled release of a compound or composition disclosed hereintherein. In some embodiments, a tablet disclosed herein furthercomprises an excipient. In some embodiments, a tablet disclosed hereinfurther comprises inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, such as microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. In some embodiments, a composition comprising a compound disclosedherein further comprises a sweetening agent, flavoring agent, coloringagent, or preserving agents.

In some embodiments, a compound or composition disclosed herein isformulated as a hard gelatin capsule. In some embodiments, a compound orcomposition disclosed herein is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin.

In some embodiments, a push-fit capsule contains a compound orcomposition disclosed herein in admixture with a filler (e.g., lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers).

In some embodiments, a soft capsule comprises a compound or compositiondisclosed herein dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, a stabilizer is added. In some embodiments, a compound orcomposition disclosed herein is mixed with a water soluble carrier suchas polyethyleneglycol or an oil medium, for example peanut oil, liquidparaffin, or olive oil.

In some embodiments, a dragee core is provided with suitable coatings.In some embodiments, concentrated sugar solutions are used. In someembodiments, the sugar solution comprises gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide,lacquer solutions, and suitable organic solvents or solvent mixtures.

In some embodiments, a compound or composition disclosed herein isformulated as an aqueous suspension. In some embodiments, a compound orcomposition disclosed herein further comprises a suspending agent, forexample sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; or a dispersing or wetting agent (e.g., anaturally-occurring phosphatide, for example lecithin, or condensationproducts of an alkylene oxide with fatty acids, for examplepolyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for exampleheptadecaethylene-oxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. In someembodiments, a compound or composition disclosed herein furthercomprises a preservative, for example ethyl, or n-propylp-hydroxybenzoate; a coloring agent; a flavoring agents; a sweeteningagent, such as sucrose, saccharin or aspartame; or combinations thereof.

In some embodiments, a compound or composition disclosed herein isformulated as an oily suspension. In some embodiments, an oilysuspension is formulated by suspending a compound or compositiondisclosed herein in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Insome embodiments, a composition or compound disclosed herein furthercomprises a thickening agent, for example beeswax, hard paraffin orcetyl alcohol. In some embodiments, a composition or compound disclosedherein further comprises a sweetening agent, a flavoring agent, or acombination thereof. In some embodiments, a composition or compounddisclosed herein further comprises an anti-oxidant such as butylatedhydroxyanisol or alpha-tocopherol.

In some embodiments, a compound or composition disclosed herein isformulated as an oil-in-water emulsion. In some embodiments, the oilyphase is a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. In someembodiments, an oil-in-water emulsion comprises an emulsifying agent. Insome embodiments, the emulsifying agent is a naturally-occurringphosphatides, for example soy bean lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate, and condensation products of the the partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate. Insome embodiments, a composition disclosed herein further comprises asweetening agent, flavoring agent, preservative, or antioxidant.

In some embodiments, a composition or compound disclosed herein isformulated as a syrup or elixir. In some embodiments, a syrup or elixirfurther comprises a sweetening agent, for example glycerol, propyleneglycol, sorbitol or sucrose. In some embodiments, a syrup or elixirfurther comprises a demulcent, a preservative, a flavoring agent, acoloring agent, and antioxidant, or a combination thereof.

In some embodiments, a compound or composition disclosed herein isformulated for parenteral administration (e.g., by bolus injection orcontinuous infusion). In some embodiments, a formulation for parenteraladministration comprises suspending agents (fatty oils such as sesameoil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes), thickening agents (e.g., sodiumcarboxymethyl cellulose, sorbitol, or dextran), stabilizing agents,dispersing agents, or combinations thereof. In some embodiments, aformulation for parenteral administration further comprises anantioxidant, buffer, bacteriostat, solute which render the formulationisotonic with blood, or a combination thereof. In some embodiments, aformulation for injection further comprises a preservative.

In some embodiments, a formulation for parenteral administration is anaqueous solution. In some embodiments, a formulation for parenteraladministration comprises water, Ringer's solution, or isotonic sodiumchloride solution.

In some embodiments, a formulation for parenteral administration is inthe form of an oil-in-water micro-emulsion where a compound orcomposition disclosed herein is dissolved in the oily phase. In someembodiments, the oily phase comprises a mixture of soybean oil andlecithin. In some embodiments, the oily phase is introduced into a waterand glycerol mixture and processed to form a microemulsion.

In some embodiments, a formulation for parenteral administration isadministered into a patient's blood-stream by local bolus injection. Insome embodiments, a continuous intravenous delivery device is utilized.An example of such a device is the Deltec CADD-PLUS™ model 5400intravenous pump.

In some embodiments, a formulation for parenteral administration ispresented in unit-dose or multi-dose containers, for example sealedampoules and vials. In some embodiments, a formulation for parenteraladministration is stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water, priorto use. In some embodiments, a formulation for parenteral administrationextemporaneous injection solutions and suspensions are prepared fromsterile powders, granules and tablets of the kind previously described.

In some embodiments, a compound or composition disclosed herein isformulated as a depot preparation. In some embodiments, a depotpreparation is administered by implantation (for example subcutaneouslyor intramuscularly) or by intramuscular injection. In some embodiments,a compound or composition disclosed herein is formulated with anysuitable polymeric or hydrophobic material (e.g., emulsion in anacceptable oil), ion exchange resin. In some embodiments, a compounddisclosed herein is formulated as a sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In some embodiments, a compound or composition disclosed herein isformulated for buccal or sublingual administration. In some embodiments,a compound or composition disclosed herein is in the form of a tablet,lozenge, pastille, or gel. In some embodiments, formulation for buccalor sublingual administration further comprises a flavoring agent (e.g.,sucrose, acacia, or tragacanth).

In some embodiments, a compound or composition disclosed herein isformulated for rectal administration (e.g., as a suppository orretention enema). In some embodiments, a compound or compositiondisclosed herein is formulated as a suppository. In some embodiments, arectal formulation comprises a non-irritating excipient which is solidat ordinary temperatures but liquid at the rectal temperature. In someembodiments, a rectal formulation comprises cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

In some embodiments, a compound or composition disclosed herein isadministered topically, that is by non-systemic administration. In someembodiments, a compound or composition disclosed herein is administeredto the epidermis or the buccal cavity. In some embodiments, a compoundor composition disclosed herein is formulated as a gel, liniment,lotion, cream, ointment, paste, or solution (e.g., as drops suitable foradministration to the eye, ear or nose). In some embodiments, compounddisclosed herein comprises from about 0.001% to 10% w/w of a topicalformulation. In some embodiments, compound disclosed herein comprisesfrom about 1% to 2% by weight of a topical formulation. In someembodiments, compound disclosed herein comprises about 10% w/w of atopical formulation; preferably, less than 5% w/w; more preferably from0.1% to 1% w/w.

In some embodiments, a pharmaceutical formulation for administration byinhalation is delivered from an insufflator, nebulizer pressurized packsor other means of delivering an aerosol spray. In some embodiments, apressurized pack comprises a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, or carbon dioxide). In some embodiments, adevice for administering an inhalable formulation comprises a meter. Insome embodiments, a pharmaceutical formulation for administration byinhalation is in the form of a dry powder composition, for example apowder mix of the compound and a suitable powder base such as lactose orstarch. In some embodiments, the powder composition is presented in unitdosage form, in for example, capsules, cartridges, gelatin or blisterpacks from which the powder is administered with the aid of an inhalatoror insufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Doses

Disclosed herein, in certain embodiments, are methods of treating adisorder characterized by abberant levels of uric acid is a tissue. Insome embodiments, the method involves administration of a composition orformulation disclosed herein in an effective amount. In someembodiments, the method involves administration of a composition orformulation disclosed herein in a therapeutically effective amount.

The effective amount of a compound, composition, or formulationdisclosed herein will firstly be dependent on the mammal being treated.In the instances where the compound, composition, or formulationdisclosed herein is administered to a human, the daily dosage willnormally be determined by the prescribing physician with the dosagegenerally varying according to the age, sex, diet, weight, generalhealth and response of the individual patient, the severity of thepatient's symptoms, the precise indication or condition being treated,the severity of the indication or condition being treated, time ofadministration, route of administration, the disposition of thecomposition, rate of excretion, drug combination, and the discretion ofthe prescribing physician. In some embodiments, treatment is initiatedwith smaller dosages which are less than the optimum dose; thereafter,the dosage is increased by small amounts until the optimum effect underthe circumstances is reached. In some embodiments, the total dailydosage is divided and administered in portions. The amount and frequencyof administration of the compound, composition, or formulation disclosedherein, and if applicable other therapeutic agents and/or therapies,will be regulated according to the judgment of the attending clinician.

In some embodiments, the dosage is between about 0.001 mg/kg of bodyweight to about 100 mg/kg of body weight per day (administered in singleor divided doses), more preferably at least about 0.1 mg/kg of bodyweight per day. In some embodiments, the dosage is from about 0.01 mg/kgof body weight per day to about 7000 mg/kg of body weight per day ofcompound, and preferably includes, e.g., from about 0.05 mg/kg of bodyweight per day to about 2500 mg/kg of body weight per day. In someembodiments, the dosage is from about 0.1 mg/kg of body weight per dayto 1000 mg/kg of body weight per day, from about 1 mg/kg of body weightper day to about 500 mg/kg of body weight per day, from about 1 mg/kg ofbody weight per day to about 250 mg/kg of body weight per day, fromabout 1 mg/kg of body weight per day to about 100 mg/kg of body weightper day, from about 1 mg/kg of body weight per day to about 50 mg/kg ofbody weight per day, from about 1 mg/kg of body weight per day to about20 mg/kg of body weight per day, from about 1 mg/kg of body weight perday to about 10 mg/kg of body weight per day according to the particularapplication. In some embodiments, the dosage is from about 1 mg/kg ofbody weight to about 5 mg/kg of body weight. In some embodiments, thedosage is from about 2 mg/kg of body weight to about 4 mg/kg of bodyweight. In some embodiments, the dosage is about 3 mg/kg of body weight.In some instances, dosage levels below the lower limit of theaforementioned range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect, e.g. by dividing such larger doses into several small doses foradministration throughout the day. The amount administered will varydepending on the particular IC₅₀ value of the compound used. Incombinational applications in which the compound is not the soletherapy, it may be possible to administer lesser amounts of compound andstill have therapeutic or prophylactic effect.

In certain embodiments, a dose of any compound described herein (e.g., acompound of Formula (I) or Formula (II)) that is effective for reducinguric acid levels in the blood/serum of an individual displaying aberranturic acid levels is at least 100 mg of a compound disclosed herein, atleast 200 mg of a compound disclosed herein, at least 300 mg of acompound disclosed herein, at least 400 mg of a compound disclosedherein, at least 500 mg of a compound disclosed herein, at least 600 mgof a compound disclosed herein, least 700 mg of a compound disclosedherein, at least 800 mg of a compound disclosed herein, at least 900 mgof a compound disclosed herein, or at least 1 g of a compound disclosedherein.

In certain embodiments, a dose of a compound described herein isadministered to an individual in need thereof once a day, twice a day,three times a day, four times a day or any other frequency based on thejudgement of an attending physician. In some embodiments, a dose isadministered before a meal. In some instances a dose is administeredafter a meal. In some embodiments, a dose is administered without food.

In the case wherein the individual's condition does not improve, uponthe doctor's discretion a compound disclosed herein is optionallyadministered chronically, that is, for an extended period of time,including throughout the duration of the individual's life in order toameliorate or otherwise control or limit the symptoms of theindividual's disease or condition.

In the case wherein the individual's status does improve, upon thedoctor's discretion a compound disclosed herein is optionally givencontinuously; alternatively, the dose of drug being administered istemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday optionallyvaries between 2 days and 1 year, including by way of example only, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days,20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350days, or 365 days. The dose reduction during a drug holiday includesfrom 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%.

Once improvement of the individual's disease has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of thesymptoms, to a level at which the improved disease, disorder orcondition is retained. In some embodiments, patients requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

Combination Therapies

In some embodiments, a compound or composition disclosed herein isadministered as a sole therapy. In some embodiments, a compound orcomposition disclosed herein is administered in combination with anadditional active agent.

In some embodiments, the therapeutic effectiveness of a compounddisclosed herein is enhanced by administration of an adjuvant. In someembodiments, the benefit experienced by an individual is increased byadministering a compound or composition disclosed herein with anothertherapeutic agent. In some embodiments, the therapeutic effectiveness ofa compound disclosed herein is enhanced by administration ofphysiotherapy, psychotherapy, radiation therapy, application ofcompresses to a diseased area, rest, altered diet, and the like.

By way of example only, in a treatment for gout the therapeuticeffectiveness of a compound disclosed herein is increased by alsoproviding the patient with another therapeutic agent for gout. Or, byway of example only, if one of the side effects experienced by a patientupon receiving one of a compound disclosed herein is nausea, then ananti-nausea agent is administered in combination with the compound.

In some embodiments, a compound disclosed herein is not administered inthe same pharmaceutical composition as the additional therapeutic agent.In some embodiments, a compound disclosed herein is administered by adifferent route than the additional therapeutic agent. For example, acompound or composition disclosed herein is administered orally, whilethe additional therapeutic agent is administered intravenously.

In some embodiments, a compound or composition disclosed herein and anadditional therapeutic agent (or additional therapy) are administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol), sequentially or dosed separately.

The particular choice of compound and other therapeutic agent willdepend upon the diagnosis of the attending physicians and their judgmentof the condition of the individual and the appropriate treatmentprotocol. In some embodiments, the additional agent is a URAT 1inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, axanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase(PNP) inhibitor, a uric acid transporter inhibitor, a glucosetransporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrierfamily 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor,an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, orcombinations thereof. In certain instances, URAT 1 is an ion exchangerthat mediates urate transportation. In certain instances, URAT Imediates urate transportation in the proximal tubule. In certaininstances, URAT I exchanges urate in a proximal tubule for lactate andnicotinate. In certain instances, xanthine oxidase oxidizes hypoxanthineto xanthine, and further to uric acid. In certain instances, xanthinedehydrogenase catalyzes the conversion of xanthine, NAD⁺, and H₂O intourate, NADH, and H⁺. In some embodiments, the additional agent isallopurinol, febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid),FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile),probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids,nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropichormone (ACTH), colchicine, a glucorticoid, an androgen, a cox-2inhibitor, a PPAR agonist, naproxen, sevelamer, sibutmaine,troglitazone, proglitazone, another uric acid lowering agent, losartan,fibric acid, benziodarone, salicylate, anlodipine, vitamin C, orcombinations thereof.

Diseases

Described herein are methods of treating a disease in an individualsuffering from the disease comprising administering to the individual aneffective amount of a composition comprising a compound disclosed hereinor a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Also described herein are methods of preventing or delaying onset of adisease in an individual at risk for developing the disease comprisingadministering to the individual an effective amount to prevent or delayonset of the disease, of a composition comprising a compound disclosedherein or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof

Further described herein are methods for the prophylaxis or treatment ofany disease or disorder in which aberrant levels of uric acid plays arole including, without limitation: hyperuricemia, gout, goutyarthritis, inflammatory arthritis, kidney disease, nephrolithiasis(kidney stones), joint inflammation, deposition of urate crystals injoints, urolithiasis (formation of calculus in the urinary tract),deposition of urate crystals in renal parenchyma, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, gout flare, tophaceous gout, kidney failure,or combinations thereof in a human or other mammal. The methodsdisclosed herein extend to such a use and to the use of the compoundsfor the manufacture of a medicament for treating such diseases ordisorders. Further, the methods disclosed herein extend to theadministration to a human an effective amount of a compound disclosedherein for treating any such disease or disorder.

Individuals that are able to be treated with a compound describedherein, or a pharmaceutically acceptable salt, ester, prodrug, solvate,hydrate or derivative of the compound, according to the methods of thisinvention include, for example, individuals that have been diagnosed ashaving gout, gouty arthritis, inflammatory arthritis, kidney disease,nephrolithiasis (kidney stones), joint inflammation, deposition of uratecrystals in joints, urolithiasis (formation of calculus in the urinarytract), deposition of urate crystals in renal parenchyma, Lesch-Nyhansyndrome, Kelley-Seegmiller syndrome, gout flare, tophaceous gout,kidney failure, or combinations thereof.

In some embodiments, an individual having an aberrant uric acid level isadministered an amount of at least one compound disclosed hereinsufficient to modulate the aberrant uric acid level (e.g., to amedically-acceptable level). In some embodiments, an individual treatedwith a compound disclosed herein displays aberrant uric acid levelswherein the uric acid levels in blood exceed a medically-accepted range(i.e., hyperuricemia). In some embodiments, an individual treated with acompound disclosed herein displays aberrant uric acid levels whereinuric acid levels in the blood exceed 360 μmol/L (6 mg/dL) for a femaleindividual or 400 μmol/L (6.8 mg/dL) for a male individual. In someembodiments, an individual treated with a compound disclosed hereindisplays aberrant uric acid levels wherein uric acid levels in urineexceed a medically-accepted range (i.e., hyperuricosuria). In someembodiments, an individual treated with a compound disclosed hereindisplays aberrant uric acid levels wherein uric acid levels in urineexceed 800 mg/day (in a male individual) and greater than 750 mg/day (ina female individual).

In some embodiments, an individual treated with a compound disclosedherein (1) displays aberrant uric acid levels, and (2) suffers from acardiovascular disease. In some embodiments, an individual treated witha compound disclosed herein (1) displays aberrant uric acid levels, and(2) suffers from an aneurysm; angina; atherosclerosis; a stroke;cerebrovascular disease; congestive heart failure; coronary arterydisease; and/or a myocardial infarction. In some embodiments, anindividual treated with a compound disclosed herein (1) displaysaberrant uric acid levels, and (2) displays (a) c-reactive protein (CRP)levels above about 3.0 mg/L; (b) homocysteine levels above about 15.9mmol/L; (c) LDL levels above about 160 mg/dL; (d) HDL levels below about40 mg/dL; and/or (e) serum creatinine levels above about 1.5 mg/dL.

In some embodiments, an individual treated with a compound disclosedherein (1) displays aberrant uric acid levels, and (2) suffers fromdiabetes. In some embodiments, an individual treated with a compounddisclosed herein (1) displays aberrant uric acid levels, and (2) suffersfrom Type I diabetes. In some embodiments, an individual treated with acompound disclosed herein (1) displays aberrant uric acid levels, and(2) suffers from Type II diabetes. In some embodiments, an individualtreated with a compound disclosed herein (1) displays aberrant uric acidlevels, and (2) suffers from a loss of beta cells of the islets ofLangerhans in the pancreas. In some embodiments, an individual treatedwith a compound disclosed herein (1) displays aberrant uric acid levels,and (2) suffers from insulin resistance and/or reduced insulinsensitivity. In some embodiments, an individual treated with a compounddisclosed herein (1) displays aberrant uric acid levels, and (2)displays (a) a fasting plasma glucose level ≧126 mg/dL; (b) a plasmaglucose level ≧200 mg/dL two hours after a glucose tolerance test;and/or (c) symptoms of hyperglycemia and casual plasma glucose levels≧200 mg/dL (11.1 mmol/l).

In some embodiments, an individual treated with a compound disclosedherein (1) displays aberrant uric acid levels, and (2) suffers frommetabolic syndrome. In some embodiments, an individual treated with acompound disclosed herein (1) displays aberrant uric acid levels, and(2) suffers from (a) diabetes mellitus, impaired glucose tolerance,impaired fasting glucose and/or insulin resistance, (b) at least two of(i) blood pressure: ≧140/90 mmHg; (ii) dyslipidaemia: triglycerides(TG): ≧1.695 mmol/L and high-density lipoprotein cholesterol (HDL-C)≦0.9 mmol/L (male), ≦1.0 mmol/L (female); (iii) central obesity:waist:hip ratio >0.90 (male); >0.85 (female), and/or body mass index >30kg/m2; and (iv) microalbuminuria: urinary albumin excretion ratio ≧20mg/min or albumin:creatinine ratio ≧30 mg/g. In some embodiments, anindividual treated with a compound disclosed herein (1) displaysaberrant uric acid levels, and (2) suffers from insulin resistance(i.e., the top 25% of the fasting insulin values among non-diabeticindividuals) and (b) at least two of (i) central obesity: waistcircumference ≧94 cm (male), ≧80 cm (female); (ii) dyslipidaemia: TG≧2.0 mmol/L and/or HDL-C <1.0 mmol/L or treated for dyslipidaemia; (iii)hypertension: blood pressure ≧140/90 mmHg or antihypertensivemedication; and (iv) fasting plasma glucose ≧6.1 mmol/L. In someembodiments, an individual treated with a compound disclosed herein (1)displays aberrant uric acid levels, and (2) displays at least three of(a) elevated waist circumference: Men ≧40 inches (men) and ≧35 inches(women); (b) elevated triglycerides: ≧150 mg/dL; (c) reduced HDL: <40mg/dL (men) and <50 mg/dL (women); (d) elevated blood pressure: ≧130/85mm Hg or use of medication for hypertension; and (e) elevated fastingglucose: ≧100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.

In some embodiments, an individual treated with a compound disclosedherein (1) displays aberrant uric acid levels, and (2) suffers fromkidney disease or kidney failure. In some embodiments, an individualtreated with a compound disclosed herein (1) displays aberrant uric acidlevels, and (2) displays oliguria (decreased urine production. In someembodiments, an individual treated with a compound disclosed herein (1)displays aberrant uric acid levels, and (2) produces less than 400 mLper day of urine (adults), produces less than 0.5 mL/kg/h of urine(children), or produces less than 1 mL/kg/h of urine (infants).

Uric Acid

Disclosed herein, in certain embodiments, is a method of reducing uricacid levels in the tissue of an individual in need thereof

In some embodiments, the method reduces uric acid levels in theblood/serum of an individual in need thereof. In some embodiments, acompound disclosed herein reduces uric acid levels in an individual inneed thereof by about 110 μmol/L to about 140 μmol/L from the uric acidlevels in the blood/serum of the individual prior to administration ofthe compound. In some embodiments, a compound disclosed herein reducesuric acid levels in an individual in need thereof by about 120 μmol/L toabout 130 μmol/L from the uric acid levels in the blood/serum of theindividual prior to administration of the compound. In some embodiments,a compound disclosed herein reduces uric acid levels in an individual inneed thereof by about 125 μmol/L to about 135 μmol/L from the uric acidlevels in the blood/serum of the individual prior to administration ofthe compound.

In some embodiments, the method reduces uric acid levels in theblood/serum of an individual in need thereof. In some embodiments, acompound disclosed herein reduces uric acid levels in an individual inneed thereof by about 25 μmol/L, about 30 about μmol/L, about 40 μmol/L,about 50 μmol/L, about 60 μmol/L, about 70 μmol/L, about 75 μmol/L,about 80 μmol/L, about 85 μmol/L, about 90 μmol/L, about 95 μmol/L,about 100 μmol/L, about 105 μmol/L, about 110 μmol/L, about 115 μmol/L,about 120 μmol/L, about 125 μmol/L, about 130 μmol/L, about 135 μmol/L,about 140 μmol/L, about 145 μmol/L, about 150 μmol/L, about 155 μmol/L,about 160 μmol/L, about 165 μmol/L, about 170 μmol/L, about 175 μmol/L,about 180 μmol/L, about 185 μmol/L, about 190 μmol/L, about 195 μmol/L,about 200 μmol/L, about 205 μmol/L, about 210 μmol/L, about 215 μmol/L,about 220 μmol/L, about 225 μmol/L, about 230 μmol/L, about 235 μmol/L,about 240 μmol/L, about 245 μmol/L, or about 250 μmol/L, compared to theuric acid levels in the blood/serum of the individual prior toadministration of the compound.

In certain instances, purines (i.e., adenine, guanine), derived fromfood or tissue turnover (cellular nucleotides undergo continuousturnover), are catabolized in humans to their final oxidation product,uric acid. In certain instances, guanine is oxidized to xanthine, whichis turn is further oxidized to uric acid by the action of xanthineoxidase; adenosine is converted to inosine which is further oxidized tohypoxanthine. In certain instances, xanthine oxidase oxidizeshypoxanthine to xanthine, and further to uric acid. In certaininstances, as part of the reverse process, the enzymehypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages guanineand hypoxanthine.

In certain instances, the keto form of uric acid is in equilibrium withthe enol form which loses a proton at physiological pH to form urate. Incertain instances, (e.g., under serum conditions (pH 7.40, 37° C.)),about 98% of uric acid is ionized as the monosodium urate salt. Incertain instances, urate is a strong reducing agent and potentantioxidant. In humans, about half the antioxidant capacity of plasmacomes from uric acid.

In certain instances, most uric acid dissolves in blood and passes tothe kidneys, where it is excreted by glomerular filtration and tubularsecretion. In certain instances, a substantial fraction of uric acid isreabsorbed by the renal tubules. One of the peculiar characteristics ofthe uric acid transport system is that, although the net activity oftubular function is reabsorption of uric acid, the molecule is bothsecreted and reabsorbed during its passage through the nephron. Incertain instances, reabsorption dominates in the S1 and S3 segments ofthe proximal tubule and secretion dominates in the S2 segment. Incertain instances, the bidirectional transport results in drugs thatinhibit uric acid transport decreasing, rather than increasing, theexcretion of uric acid, compromising their therapeutic usefulness. Incertain instances, normal uric acid levels in human adults (5.1+/−0.93mg/dL) are close to the limits of urate solubility (˜7 mg/dL at 37° C.),which creates a delicate physiologic urate balance. In certaininstances, the normal uric acid range for females is approximately 1mg/dL below the male range.

Hyperuricemia

In certain instances, hyperuricemia is characterized by higher thannormal blood levels of uric acid, sustained over long periods of time.In certain instances, increased blood urate levels may be due toenhanced uric acid production (˜10-20%) and/or reduced renal excretion(˜80-90%) of uric acid. In certain instances, causes of hyperuricemiamay include:

-   Obesity/weight gain-   Excessive alcohol use-   Excessive dietary purine intake (foods such as shellfish, fish roe,    scallops, peas lentils, beans and red meat, particularly    offal—brains, kidneys, tripe, liver)-   Certain medications, including low-dose aspirin, diuretics, niacin,    cyclosporine, pyrazinamide, ethambutol, some high blood pressure    drugs and some cancer chemotherapeutics, immunosuppressive and    cytotoxic agents-   Specific disease states, particularly those associated with a high    cell turnover rate (such as malignancy, leukemia, lymphoma or    psoriasis), and also including high blood pressure, hemoglobin    diseases, hemolytic anemia, sickle cell anemia, various    nephropathies, myeloproliferative and lymphoproliferative diseases,    hyperparathyroidism, renal disease, conditions associated with    insulin resistance and diabetes mellitus, and in transplant    recipients, and possibly heart disease-   Inherited enzyme defects-   Abnormal kidney function (e.g. increased ATP turn over, reduced    glomerular urate filtration)-   Exposure to lead (plumbism or “saturnine gout”)

In certain instances, hyperuricemia may be asymptomatic, though isassociated with the following conditions: gout, gouty arthritis, uricacid stones in the urinary tract (urolithiasis), deposits of uric acidin the soft tissue (tophi), deposits of uric acid in the kidneys (uricacid nephropathy), and impaired kidney function, possibly leading tochronic and acute renal failure.

Gout

Prevalence

The incidence of gout has increased over the past two decades and, inthe United States, affects as much as 2.7% of the population aged 20years and older, totaling over 5.1 million American adults. Gout is morecommon in men than women, (3.8% or 3.4 million men vs. 1.6% or 1.7million women), typically affecting men in their 40's and 50's (althoughgout attacks can occur after puberty which sees an increase in uric acidlevels). An increase in prevalence of gout from 2.9 to 5.2 per 1000 inthe time period 1990 to 1999 was observed, with most of the increaseoccurring in those over the age of 65. Gout attacks are more common inwomen after menopause. In certain instances, gout is one of the mostcommon forms of arthritis, accounting for approximately 5% of allarthritis cases. In certain instances, kidney failure and urolithiasisoccur in 10-18% of individuals with gout and are common sources ofmorbidity and mortality from the disease.

Leading Causes

In most cases, gout is associated with hyperuricemia. In certaininstances, individuals suffering from gout excrete approximately 40%less uric acid than nongouty individuals for any given plasma urateconcentration. In certain instances, urate levels increase until thesaturation point is reached. In certain instances, precipitation ofurate crystals occurs when the saturation point is reached. In certaininstances, these hardened, crystallized deposits (tophi) form in thejoints and skin, causing joint inflammation (arthritis). In certaininstances, deposits are be made in the joint fluid (synovial fluid)and/or joint lining (synovial lining). Common areas for these depositsare the large toe, feet, ankles and hands (less common areas include theears and eyes). In certain instances, the skin around an affected jointbecomes red and shiny with the affected area being tender and painful totouch. In certain instances, gout attacks increase in frequency. Incertain instances, untreated acute gout attacks lead to permanent jointdamage and disability. In certain instances, tissue deposition of urateleads to: acute inflammatory arthritis, chronic arthritis, deposition ofurate crystals in renal parenchyma and urolithiasis. In certaininstances, the incidence of gouty arthritis increases 5 fold inindividuals with serum urate levels of 7 to 8.9 mg/dL and up to 50 foldin individuals with levels >9 mg/dL (530 μmol/L). In certain instances,individuals with gout develop renal insufficiency and end stage renaldisease (i.e., “gouty nephropathy”). In certain instances, goutynephropathy is characterized by a chronic interstitial nephropathy,which is promoted by medullary deposition of monosodium urate.

In certain instances, gout includes painful attacks of acute,monarticular, inflammatory arthritis, deposition of urate crystals injoints, deposition of urate crystals in renal parenchyma, urolithiasis(formation of calculus in the urinary tract), and nephrolithiasis(formation of kidney stones). In certain instances, secondary goutoccurs in individuals with cancer, particularly leukemia, and those withother blood diseases (e.g. polycythemia, myeloid metaplasia, etc).

Symptoms

In certain instances, attacks of gout develop very quickly, frequentlythe first attack occurring at night. In certain instances, symptomsinclude sudden, severe joint pain and extreme tenderness in the jointarea, joint swelling and shiny red or purple skin around the joint. Incertain instances, the attacks are infrequent lasting 5-10 days, with nosymptoms between episodes. In certain instances, attacks become morefrequent and last longer, especially if the disease is not controlled.In certain instances, episodes damage the affected joint(s) resulting instiffness, swelling, limited motion and/or persistent mild to moderatepain.

Treatment

In certain instances, gout is treated by lowering the production of uricacid. In certain instances, gout is treated by increasing the excretionof uric acid. In certain instances, gout is treated by URAT 1, xanthineoxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purinenucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT)inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, asolute carrier family 2 (facilitated glucose transporter), member 9(SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, anOAT-4 inhibitor, or combinations thereof. In general, the goals of gouttreatment are to i) reduce the pain, swelling and duration of an acuteattack, and ii) prevent future attacks and joint damage. In certaininstances, gout attacks are treated successfully using a combination oftreatments. In certain instances, gout is one of the most treatableforms of arthritis.

i) Treating the gout attack. In certain instances, the pain and swellingassociated with an acute attack of gout can be addressed withmedications such as acetaminophen, steroids, nonsteroidalanti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) orcolchicine. In certain instances, proper medication controls gout within12 to 24 hours and treatment is stopped after a few days. In certaininstances, medication is used in conjunction with rest, increased fluidintake, ice-packs, elevation and/or protection of the affected area/s.In certain instances, the aforementioned treatments do not preventrecurrent attacks and they do not affect the underlying diseases ofabnormal uric acid metabolism.

ii) Preventing future attacks. In certain instances, reducing serum uricacid levels below the saturation level is the goal for preventingfurther gout attacks. In some cases, this is achieved by decreasing uricacid production (e.g. allopurinol), or increasing uric acid excretionwith uricosuric agents (e.g. probenecid, sulfinpyrazone, benzbromarone).

In certain instances, allopurinol inhibits uric acid formation,resulting in a reduction in both the serum and urinary uric acid levelsand becomes fully effective after 2 to 3 months.

In certain instances, allopurinol is a structural analogue ofhypoxanthine, (differing only in the transposition of the carbon andnitrogen atoms at positions 7 and 8), which inhibits the action ofxanthine oxidase, the enzyme responsible for the conversion ofhypoxanthine to xanthine, and xanthine to uric acid. In certaininstances, it is metabolized to the corresponding xanthine analogue,alloxanthine (oxypurinol), which is also an inhibitor of xanthineoxidase. In certain instances, alloxanthine, though more potent ininhibiting xanthine oxidase, is less pharmaceutically acceptable due tolow oral bioavailability. In certain instances, fatal reactions due tohypersensitivity, bone marrow suppression, hepatitis, and vasculitishave been reported with Allopurinol. In certain instances, the incidenceof side effects may total 20% of all individuals treated with the drug.Treatment for diseases of uric acid metabolism has not evolvedsignificantly in the following two decades since the introduction ofallopurinol.

In certain instances, uricosuric agents (e.g., probenecid,sulfinpyrazone, and benzbromarone) increase uric acid excretion. Incertain instances, probenecid causes an increase in uric acid secretionby the renal tubules and, when used chronically, mobilizes body storesof urate. In certain instances, 25-50% of individuals treated withprobenecid fail to achieve reduction of serum uric acid levels <6 mg/dL.In certain instances, insensitivity to probenecid results from drugintolerance, concomitant salicylate ingestion, and renal impairment. Incertain instances, one-third of the individuals develop intolerance toprobenecid. In certain instances, administration of uricosuric agentsalso results in urinary calculus, gastrointestinal obstruction, jaundiceand anemia.

Plumbism or “Saturnine Gout”

In certain instances, excessive exposure to lead (lead poisoning orplumbism) results in “saturnine gout,” a lead-induced hyperuricemia thatresults from lead inhibition of tubular urate transport causingdecreased renal excretion of uric acid. In certain instances, more than50% of individuals suffering from lead nephropathy suffer from gout. Incertain instances, acute attacks of saturnine gout occur in the kneemore frequently than the big toe. In certain instances, renal disease ismore frequent and more severe in saturnine gout than in primary gout. Incertain instances, treatment consists of excluding the individual fromfurther exposure to lead, the use of chelating agents to remove lead,and control of acute gouty arthritis and hyperuricaemia. In certaininstances, saturnine gout is characterized by less frequent attacks thanprimary gout. In certain instances, lead-associated gout occurs inpre-menopausal women, an uncommon occurrence in non lead-associatedgout.

Lesch-Nyhan Syndrome

In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's syndrome)affects about one in 100,000 live births. In certain instances, LNS iscaused by a genetic deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT). In certain instances, LNS is anX-linked recessive disease. In certain instances, LNS is present atbirth in baby boys. In certain instances, the disease leads to severegout, poor muscle control, and moderate mental retardation, which appearin the first year of life. In certain instances, the disease alsoresults in self-mutilating behaviors (e.g., lip and finger biting, headbanging) beginning in the second year of life. In certain instances, thedisease also results in gout-like swelling in the joints and severekidney problems. In certain instances, the disease leads neurologicalsymptoms include facial grimacing, involuntary writhing, and repetitivemovements of the arms and legs similar to those seen in Huntington'sdisease. The prognosis for individuals with LNS is poor. In certaininstances, the life expectancy of an untreated individual with LNS isless than about 5 years. In certain instances, the life expectancy of atreated individual with LNS is greater than about 40 years of age.

Hyperuricemia and Other Diseases

In certain instances, hyperuricemia is found in individuals withcardiovascular disease (CVD) and/or renal disease. In certain instances,hyperuricemia is found in individuals with prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.In certain instances, hyperuricemia is found in individuals with obesity(e.g., central obesity), high blood pressure, hyperlipidemia, and/orimpaired fasting glucose. In certain instances, hyperuricemia is foundin individuals with metabolic syndrome. In certain instances, goutyarthritis is indicative of an increased risk of acute myocardialinfarction. In some embodiments, administration of a compound describedherein to an individual are useful for decreasing the likelihood of aclinical event associated with a disease or condition linked tohyperuricemia, including, but not limited to, prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome,endothelial dysfunction, oxidative stress, elevated renin levels,elevated endothelin levels, and/or elevated C-reactive protein levels.

In some embodiments, a compound described herein is administered to anindividual suffering from a disease or condition requiring treatmentwith a diuretic. In some embodiments, a compound described herein areadministered to an individual suffering from a disease or conditionrequiring treatment with a diuretic, wherein the diuretic causes renalretention of urate. In some embodiments, the disease or condition iscongestive heart failure or essential hypertension.

In some embodiments, administration of a compound described herein to anindividual is useful for improving motility or improving quality oflife.

In some embodiments, administration of a compound described herein to anindividual is useful for treating or decreasing the side effects ofcancer treatment.

In some embodiments, administration of a compound described herein to anindividual is useful for decreasing kidney toxicity of cis-platin.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

I Chemical Syntheses Example 1A2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid

Step A: 4-Isothiocyanato-1-naphthonitrile

Thiophosgene (9.1 mL, 118.9 mmol) was added to a stirring slurry of4-amino-1-naphthalenecarbonitrile (10 g, 59.45 mmol) in dichloromethane(200mL) and saturated aqueous NaHCO₃ solution (200 mL) at 0° C., and themixture stirred for 3 days at room temp. The layers were separated andthe organic layer concentrated to provide4-isothiocyanato-1-naphthonitrile as a tan solid (11.64 g, 93%).

Step B: 4-(2-Mercapto-1H-imidazol-1-yl)-1-naphthonitrile

Aminoacetaldehyde dimethyl acetal (5.98 mL, 55.36 mmol) was added to astirring slurry of 4-isothiocyanato-1-naphthonitrile (11.64 g, 55.36mmol) in dioxane (55 mL), and stirring continued for 1 h (sizeableexotherm observed). HCl was added (4.8 mL, 58.13 mmol) and the mixtureheated to 105° C. for 18 h. The mixture was then concentrated, methanoladded (100 mL), concentrated again, more methanol added (100 mL) andsonicated. Filtration provided4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile as a tan solid (8.33 g,60%).

Step C: Ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate

Triethylamine (4.92 mL, 35.32 mmol), followed by ethyl bromoacetate(3.74 mL, 33.72 mmol) were added to a stirring slurry of4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (8.07 g, 32.11 mmol) indichloromethane (60 mL) and stirring continued for 3 h. The mixture waswashed with aqueous HCl solution (0.2M 100 mL), 50% saturated sodiumchloride solution (50 mL), dried over sodium sulfate, filtered, andconcentrated. Hexanes (100 mL) were added and the mixture concentratedto provide ethyl2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as alight-tan solid (10.47 g, (97%).

Step D: Ethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate

N-bromosuccinimide (5.48 g, 30.82 mmol) was added in three portions to asolution of ethyl2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (10.40 g,30.82 mmol) in dichloromethane (150 mL) at 0° C. and then stirred atroom temperature for 18 h. The mixture was washed with water (2×50 mL),saturated aqueous sodium chloride solution (50 mL), dried over sodiumsulfate, filtered and concentrated. Purification by columnchromatography (0-50% EtOAc/hexanes) provided ethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as anoff-white solid (9.18 g, 71.5%).

Step E:2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid

Aqueous lithium hydroxide solution (1M, 44 mL, 44.00 mmol) was added toa solution of ethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (9.14g, 21.96 mmol) in THF (60 mL), ethanol (24 mL) and water (20 mL), andstirred for 4 h. After concentrating, the residue was acidified withaqueous HCl solution (1N, 50 mL), diluted with water (100 mL) andfiltered to afford2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidas an off-white solid (8.52 g, 100%).

Example 1B

Step 1: The thioimidazole compound is dissolved in DMF (0.5 M finalconcentration), cooled to 0° C. and potassium carbonate (1 equivalent)is added. After stirring for 5 min, methyl iodide (1.0 equivalent) isadded and the reaction allowed to stir until thin-layer chromatographyshows no starting material remains. The reaction mixture is thenconcentrated under reduced pressure and the residue extracted betweensat. NaHCO₃ and ethyl acetate. The crude product is used in Step 2.

Step 2: The methylthioether compound is dissolved absolute ethanol (0.2M final concentration). Ammonium molybdate tetrahydrate((NH₄)₆Mo₇O₂₄.4H₂O) 0.3 equivalents) and hydrogen peroxide (10equivalents of 30% aqueous solution) are added and the reaction mixtureis stirred at room temperature until no starting material remains. Thereaction mixture is then concentrated under reduced pressure and theresidue is extracted between water and ethyl acetate. The combinedorganic extracts are dried and purified by chromatography to give themethylsulfone product.

Step 3: The methylsulfone compound is dissolved in DMF (0.5 M finalconcentration), cooled to 0° C. and sodium hydride (1 equivalent) isadded. After stirring for 5 min, methyl glycolate (1.0 equivalent) isadded and the reaction allowed to stir until thin-layer chromatographyshows no starting material remains. The reaction mixture is quenchedwith sat. NaHCO₃, the resulting mixture is concentrated under reducedpressure. The residue is extracted with ethyl acetate and the combinedorganic extracts are dried, concentrated and purified by chromatography.

Similar synthetic methods are optionally utilized to prepare othercompounds having various naphthyl and/or imidazolyl substituents.

Example 2 Ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetate

Glycine ethyl ester hydrochloride (76 mg, 0.541 mmol, 1.2 equiv.),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg,0.676 mmol, 1.5 equiv.), 1-hydroxy-7-azabenzotriazole (92 mg, 0.676mmol, 1.5 equiv.) and 2,6-lutidine (0.16 mL, 1.35 mmol, 3.0 equiv) wereadded to a solution of2-(5-bromo-1-(4-cyanonaphthalen-l-yl)-1H-imidazol-2-ylthio)acetic acid(175 mg, 0.451 mmol) in dichloromethane (2.25 mL) and stirred at roomtemperature for 18 hours. The crude product was purified by SGC (0-100%ethyl acetate/hexanes) to afford the title compound containing some1-hydroxy-7-azabenzotriazole. The impure product was dissolved in ethylacetate (50 mL), washed with aqueous HCl solution (0.1M, 2×30 mL),saturated aqueous NaHCO₃ solution (30 mL), and saturated sodium chloridesolution (30 mL). The organics were dried over sodium sulfate, filtered,and concentrated to afford ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetateas a yellow oil (199 mg, 93%).

Example 32-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid

Aqueous lithium hydroxide solution (1M, 0.47 mL, 0.473 mmol) was addedto a solution of ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetae(112 mg, 0.237 mmol) in 3:1, THF/water (0.95 mL) and stirred for 18 h atroom temperature. After concentrating, the crude reaction mixture wasacidified with aqueous HCl solution (1M 1.2 mL), diluted with water (10mL), stirred to break up solids, and filtered to afford2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid as an off-white solid (99 mg, 94%).

Example 4 Ethyl3-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate

Ethyl3-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acidwith β-alanine ethyl ester according to the procedure described inexample 2.

Example 5 (2S)-Ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate

(2S)-ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acidwith alanine ethyl ester according to the procedure described in example2.

Example 6 (2S)-Ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoate

(2S)-ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido-3-methylbutanoatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acidwith valnine ethyl ester according to the procedure described in example2.

Example 73-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoicacid

3-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoicacid was prepared by hydrolysis of ethyl3-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate(prepared as described herein), according to the procedure described inexample 3.

Example 8(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoicacid

(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoicacid was prepared by hydrolysis of (2S)-ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate (prepared as described herein), according to the proceduredescribed in example 3.

Example 9(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoicacid

(2S)-2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoicacid was prepared by hydrolysis of (2S)-ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylbutanoate(prepared as described herein), according to the procedure described inexample 3.

Example 102-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid

Step A: Ethyl2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate

Triethylamine (1.1 eq), followed by ethyl 2-bromo-2,2-difluoroacetate(1.05 eq) were added to a stirring slurry of4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (prepared as describedherein, 1 eq) in dichloromethane and stirring continued for 3 h. Themixture was washed with aqueous HCl solution (0.2M), 50% saturatedsodium chloride solution, dried over sodium sulfate, filtered, andconcentrated. Hexanes were added and the mixture concentrated to provideethyl2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.

Step B: Ethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate

N-bromosuccinimide (1 eq) was added in three portions to a solution ofethyl2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate(1 eq) in dichloromethane at 0° C. and then stirred at room temperaturefor 18 h. The mixture was washed twice with water and once withsaturated aqueous sodium chloride solution, dried over sodium sulfate,filtered and concentrated. Purification by column chromatography (0-50%ethyl actetae/hexanes) provided ethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.

Step C:2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid

Aqueous lithium hydroxide solution (1M, 2 eq) was added to a solution ofethyl2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate(1 eq) in THF, ethanol and water, and stirred for 4 h. Afterconcentrating, the residue was acidified with aqueous HCl solution (1N),diluted with water and filtered to afford2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid.

Example 11 ^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetate

^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid with glycine ^(t)butyl ester according to the procedure describedin example 2.

Example 12 (2S)-^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)propanoate

(2S)-^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)propanoatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid with alanine ^(t)butyl ester according to the procedure describedin example 2.

Example 13 (2S)-^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylbutanoate

(2S)-^(t)Butyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylbutanoatewas prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid with valine ^(t)butyl ester according to the procedure described inexample 2.

Example 142-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid

2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid was prepared by hydrolysis of ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetate(prepared as described herein), according to the procedure described inexample 3.

Example 15(2S)-2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)propanoicacid

(2S)-2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)propanoicacid was prepared by hydrolysis of (2S)-ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)propanoate(prepared as described herein), according to the procedure described inexample 3.

Example 16(2S)-2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylbutanoicacid

(2S)-2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylbutanoicacid was prepared by hydrolysis of (2S)-Ethyl2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylbutanoate(prepared as described herein), according to the procedure described inexample 3.

Example 172-(2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetamido)aceticacid

2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetamido)aceticacid is prepared via either of the two routes shown below. In the first,2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid (see eg 3) is coupled with glycine ethyl ester and then hydrolyzedto the acid. In the second,2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(see eg 1) is coupled with NH₂-Gly-Gly-OEt, which is then hydrolyzed tothe acid.

Example 182-(2-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetamido)aceticacid

2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetamido)aceticacid is prepared via either of the two routes shown below. In the first,2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid (see eg 14) is coupled with glycine ethyl ester and then hydrolyzedto the acid. In the second, (see eg 10),2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid is coupled with NH₂-Gly-Gly-OEt, which is then hydrolyzed to theacid.

Examples 19-35

The following compounds are prepared by coupling2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidwith an amino acid or amino acid derivative.

Amino acid ester hydrochloride (NH₂—CH(AA)-COOEt.HCl; 1.2 equiv.),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5equiv.), 1-hydroxy-7-azabenzotriazole (1.5 equiv.) and 2,6-lutidine (3.0equiv) are added to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(1.0 equiv.) in dichloromethane and stirred at room temperature for 18hours. The crude product is purified by SGC (0-100% ethylacetate/hexanes). If any starting material remains, the product isfurther purified by dissolving in ethyl acetate (50 mL), washing withaqueous HCl solution (0.1M, 2×30 mL), saturated aqueous NaHCO₃ solution(30 mL), and saturated sodium chloride solution (30 mL). Combinedorganics are dried (sodium sulfate), filtered and concentrated.

Eg Compound Structure Compound Name 19

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-4- methylpentanoate 20

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- methylpentanoate 21

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- hydroxypropanoate 22

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- hydroxybutanoate 23

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- mercaptopropanoate 24

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- (methythio)propanoate 25

3-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-4- ethoxy-4-oxobutanoic acid 26

4-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-5- ethoxy-5-oxopentanoic acid 27

Ethyl 4-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-4- oxobutanoate 28

Ethyl 5-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-5- oxopentanoate 29

Ethyl 6-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio) acetamido)hexanoate 30

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)- 5-guanidinopentanoate 31

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- phenylpropanoate 32

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- (4-hydroxyphenyl)propanoate 33

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- (1H-imidazol-4-yl)propanoate 34

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-3- (1H-indol-3-yl)propanoate 35

Ethyl 1-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetyl) pyrrolidine-2- carboxylate

Examples 36-52

The following compounds are prepared by hydrolysis of the compoundsdescribed in examples 19-35.

Aqueous lithium hydroxide solution (1M) is added to a solution of theester in THF/water (3/1), and stirred for 18 h at room temperature.After concentrating, the crude reaction mixture is acidified withaqueous HCl solution (1M), diluted with water, stirred to break upsolids, and the solid isolated by filtration to provide the acid.

Eg Compound Structure Compound Name 36

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-4- methylpentanoic acid 37

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-methylpentanoic acid 38

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3- hydroxypropanoic acid 39

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-hydroxybutanoic acid 40

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3- mercaptopropanoic acid 41

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3- (methylthio)propanoic acid 42

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)succinic acid 43

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)pentanedioic acid 44

4-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-4-oxobutanoic acid 45

5-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)-5-oxopentanoic acid 46

6-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)hexanoic acid 47

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-5- guanidinopentanoic acid 48

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-phenylpropanoic acid 49

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-(4- hydroxyphenyl)propanoic acid 50

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-(1H-imidazol-4- yl)propanoic acid 51

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetamido)-3-(1H-indol- 3-yl)propanoic acid 52

1-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)acetyl)pyrrolidine-2- carboxylic acid

Examples 53-69

The following compounds are prepared by coupling2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid with an amino acid or amino acid derivative.

Amino acid ester hydrochloride (NH₂—CH(AA)-COOEt.HCl; 1.2 equiv.),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5equiv.), 1-hydroxy-7-azabenzotriazole (1.5 equiv.) and 2,6-lutidine (3.0equiv) are added to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid (1.0 equiv.) in dichloromethane and stirred at room temperature for18 hours. The crude product is purified by SGC (0-100% ethylacetate/hexanes). If any starting material remains, the product isfurther purified by dissolving in ethyl acetate (50 mL), washing withaqueous HCl solution (0.1M, 2×30 mL), saturated aqueous NaHCO₃ solution(30 mL), and saturated sodium chloride solution (30 mL). Combinedorganics are dried (sodium sulfate), filtered and concentrated.

Eg Compound Structure Compound Name 53

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-4- methylpentanoate 54

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- methylpentanoate 55

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- hydroxypropanoate 56

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- hydroxybutanoate 57

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- mercaptopropanoate 58

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- (methylthio)propanoate 59

3-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H- imidazol-2-ylthio)-2,2-difluoroacetamido)-4-ethoxy- 4-oxobutanoic acid 60

4-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H- imidazol-2-ylthio)-2,2-difluoroacetamido)-5-ethoxy- 5-oxopentanoic acid 61

Ethyl 4-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-4- oxobutanoate 62

Ethyl 5-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-5- oxopentanoate 63

Ethyl 6-amino-2-(2-(5-bromo-1- (4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)hexanoate 64

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-5- guanidinopentanoate 65

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3- phenylpropanoate 66

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3-(4-hydroxyphenyl)propanoate 67

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3-(1H-imidazol-4-yl)propanoate 68

Ethyl 2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)-3-(1H- indol-3-yl)propanoate69

Ethyl 1-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetyl)pyrrolidine-2- carboxylate

Examples 70-87

The following compounds are prepared by hydrolysis of the compoundsdescribed in examples 53-69.

Aqueous lithium hydroxide solution (1M) is added to a solution of theester in THF/water (3/1), and stirred for 18 h at room temperature.After concentrating, the crude reaction mixture is acidified withaqueous HCl solution (1M), diluted with water, stirred to break upsolids, and the solid isolated by filtration to provide the acid.

Eg Compound Structure Compound Name 70

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylpentanoic acid 71

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-methylpentanoic acid 72

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3- hydroxypropanoic acid 73

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3- hydroxybutanoic acid 74

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3- mercaptopropanoic acid 75

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3- (methylthio)propanoic acid 76

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)succinic acid 78

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)pentanedioic acid 79

4-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-4- oxobutanoic acid 80

5-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-5- oxopentanoic acid 81

6-amino-2-(2-(5-bromo-1-(4- cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2- difluoroacetamido)hexanoic acid 82

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-5- guanidinopentanoic acid 83

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3- phenylpropanoic acid 84

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-(4- hydroxyphenyl)propanoic acid 85

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-(1H-imidazol- 4-yl)propanoic acid 86

2-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)-3-(1H-indol-3- yl)propanoic acid 87

1-(2-(5-bromo-1-(4-cyanonaphthalen- 1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetyl)pyrrolidine-2- carboxylic acid

Example 88 Sodium2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate

Aqueous sodium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(1 eq) in ethanol at 10° C., and the mixture stirred for a further 10mins at 10° C. Solvents are removed in vacuo to dryness to provide thesodium salt.

Example 89 Lithium2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate

Aqueous lithium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(1 eq) in ethanol at 10° C., and the mixture stirred for a further 10mins at 10° C. Solvents are removed in vacuo to dryness to provide thelithium salt.

Example 902-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate salts

According to the methods described in examples 188 and 189, otherpharmaceutically acceptable salts, such as the potassium, calcium orpiperazine salts are prepared.

Example 91 Sodium2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate

Aqueous sodium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe sodium salt.

Example 92 Lithium2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate

Aqueous lithium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe lithium salt.

Example 932-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetatesalts

According to the methods described in examples 91 and 92, otherpharmaceutically acceptable salts, such as the potassium, calcium orpiperazine salts are prepared.

Example 94 Sodium2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-dffluoroacetamido)acetate

Aqueous sodium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe sodium salt.

Example 95 Lithium2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-dffluoroacetamido)acetate

Aqueous lithium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe lithium salt.

Example 962-(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-dffluoroacetamido)acetatesalts

According to the methods described in examples 94 and 95, otherpharmaceutically acceptable salts, such as the potassium, calcium orpiperazine salts are prepared.

Example 97 Sodium2-(2-(5-bromo-1-(4-cyclopropylnaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-dffluoroacetamido)acetate

Aqueous sodium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(2-(5-bromo-1-(4-cyclopropylnaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe sodium salt.

Example 98 Lithium2-(2-(5-bromo-1-(4-cyclopropylnaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetate

Aqueous lithium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(2-(5-bromo-1-(4-cyclopropylnaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)aceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe lithium salt.

Example 992-(2-(5-Bromo-1-(4-cyclopropylnaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetatesalts

According to the methods described in examples 97 and 98, otherpharmaceutically acceptable salts, such as the potassium, calcium orpiperazine salts are prepared.

Example 100 Sodium2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetamido)acetate

Aqueous sodium hydroxide solution (1M, 1 eq) is added dropwise over 5mins to a solution of2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)aceticacid (1 eq) in ethanol at 10° C., and the mixture stirred for a further10 mins at 10° C. Solvents are removed in vacuo to dryness to providethe sodium salt.

Example 101 Solubility of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid—free acid, sodium and piperazine salts

To 1.00 mL (or 0.50 mL) of test solvent in an eppendorf vial, is addedvarious weighed amounts of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid,(as the free acid, sodium and piperazine salts), and the weightsrecorded. When it appears the saturation point is being reached,addition is stopped, and the eppendorf vial is shaken at a constantspeed of 1000 rpm at 22° C. for 24 hours. The tubes are then centrifugedfor 5 minutes at 10-15,000 rpm, and checked for precipitation. Samplesare diluted with acetonitrile/water, (1/1) (or iso-propyl alcohol forhexane) and analyzed by HPLC against known standards.

Example 102 Solubility of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid—free acid, sodium and piperazine salts

To 1.00 mL (or 0.50 mL) of test solvent in an eppendorf vial, is addedvarious weighed amounts of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid, (as the free acid, sodium and piperazine salts), and the weightsrecorded. When it appears the saturation point is being reached,addition is stopped, and the eppendorf vial is shaken at a constantspeed of 1000 rpm at 22° C. for 24 hours. The tubes are then centrifugedfor 5 minutes at 10-15,000 rpm, and checked for precipitation. Samplesare diluted with acetonitrile/water, (1/1) (or iso-propyl alcohol forhexane) and analyzed by HPLC against known standards.

II Biological Evaluation Example 103 Uric Acid Uptake Assay

Creation of Stable Cell Lines Expressing hURAT1 Transporter: Full-lengthhuman URAT1 gene (SLC22A12) was subcloned from plasmid pCMV6-XL5(Origene) into eukaryotic expression plasmid pCMV6/Neo (Origene) usingNot I restriction sites. Gene sequencing confirmed the sequence ofhURAT1 as outlined in Genbank (Accession #NM_(—)144585.2). HEK293 humanembryonic kidney cells (ATCC# CRL-1573) were propagated in EMEM tissueculture medium as described by ATCC in an atmosphere of 5% CO₂ and 95%air. Transfections of HEK293 cells with the pCMV6/Neo/URAT1 constructwere performed using L2000 transfection reagent (Invitrogen) asdescribed by the manufacturer. After 24 h the transfected cells weresplit into 10 cm tissue culture plates and grown for 1 day after whichthe medium was replaced with fresh growth medium containing G418 (Gibco)at 0.5 mg/ml final concentration. Drug-resistant colonies were selectedafter approximately 8 days and then tested for ¹⁴C-uric acid transportactivity. The HEK293/urat1 cells are plated on Poly-D-Lysine Coated96-well Plates at a density of 75,000 cells per well.

Cells were grown overnight (20-26 hours) at 37° C. in an incubator.Plates were allowed to come to room temperature and media was washed outwith one wash of 250 μl of Wash Buffer (125 mM Na Gluconate, 10 mM Hepesph 7.3). Compound or vehicle is added in assay buffer with C14 Uric Acidfor a final concentration of 40 μM Uric Acid with a specific activity of54 mCi/mmol. Assay Buffer is 125 mM Sodium Gluconate, 4.8 mM PotassiumGluconate, 1.2 mM Potassium phosphate, monobasic, 1.2 mM magnesiumsulfate, 1.3 mM Ca Gluconate, 5.6 mM Glucose, 25 mM HEPES, pH 7.3.Plates were incubated at room temperature for 10 minutes then washed 3times with 50 μl Wash Buffer and 3 times with 250 μl Wash Buffer.Microscint 20 Scintillation Fluid was added and plates were incubatedovernight at 45° C. to equilibrate. Plates are then read on the TopCountPlate Reader and an EC50 value generated. (See Enomoto et al, Nature,2002, 417, 447-451 and Anzai et al, J. Biol. Chem., 2004, 279,45942-45950.).

Compounds prepared as described herein, were examined according to theprocedure described above and EC₅₀ values generated. The table belowsummarizes the activity of the compounds in the Uric Acid Uptake Assay,wherein A represents an EC₅₀ from 1 nM to 1 μM; B represents an EC₅₀from 1 μM to 30 μM; and C represents an EC₅₀ greater than 30 μM. (N/Ameans data not available).

Activity Structure NMR Chemical Shifts MS (EC₅₀)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67 (br. s., 4 H) 1.87 (s, 3 H) 2.07(d, J = 16.79 Hz, 1 H) 2.23 (br. s., 1 H) 2.70 (s, 6 H) 2.73 (br. s., 2H) 3.77 (br. s., 2 H) 6.88 (br. s., 1 H) 7.04 (s, 2 H) Mass found:346.09 (M + 1) B

¹H NMR (DMSO-d₆, 400 MHz): δ 12.84 (bs, 1H), 8.46 (d, 1H), 8.32 (d, 1H),7.98 (t, 1H), 7.87 (m, 2H), 7.46 (s, 1H), 7.30 (d, 1H). msES + (387.91,389.91) A

¹H NMR (DMSO-d₆, 400 MHz): δ 8.54 (t, 1H), 8.45 (d, 1H), 8.32 (d, 1H),7.97 (dt, 1H), 7.90 (d, 1H), 7.84 (dt, 1H), 7.46 (s, 1H), 7.29 (d, 1H),4.09 (q, 2H), 3.84 (s, 2H), 3.81 (d, 2H), 1.18 (t, 3H). Ms ES + (472.87,474.88) A

¹H NMR (DMSO-d₆, 400 MHz): δ 12.61 (bs, 1H), 8.42 (d, 1H), 8.29 (d, 1H),7.95 (dt, 1H), 7.88 (d, 1H) 7.82 (dt, 1H), 7.43 (s, 1H), 7.27 (d, 1H),3.81 (d, 2H), 3.71 (d, 2H). msES + (444.92, 446.93) B

¹H NMR (DMSO-d₆, 400 MHz): δ 8.45 (d, 1H), 8.32 (d, 1H), 8.20 (t, 1H),7.97 (dt, 1H), 7.90 (d, 1H) 7.85 (dt, 1H), 7.44 (s, 1H), 7.29 (d, 1H),4.06 (q, 2H), 3.73 (s, 2H), 3.24 (q, 2H), 2.41 (t, 2H), 1.18 (t, 3H).msES + (486.91, 488.92) A

¹H NMR (DMSO-d₆, 400 MHz): δ 8.57 (d, 1H), 8.45 (dd, 1H), 8.32 (d, 1H),7.97 (t, 1H) 7.90 (d. 1H), 7.84 (t, 1H), 7.46 (s, 1H), 7.29 (d, 1H),4.18 (q, 1H), 4.07 (m, 2H), 3.81 (m, 2H), 1.24 (t, 3H), 1.16 (t, 3H).msES + (486.91, 488.92) A

¹H NMR (DMSO-d₆, 400 MHz): δ 8.45 (m, 2H), 8.32 (d, 1H), 7.97 (t, 1H),7.89 (dd, 1H), 7.84 (dt, 1H), 7.46 (s, 1H), 7.28 (dd, 1H), 4.10 (m, 3H),3.86 (m, 2H), 2.02 (m, 1H), 1.18 (dt, 3H), 0.85 (m, 6H). msES + (514.92,516.93) A

¹H NMR (DMSO-d₆, 400 MHz): δ 12.23 (bs, 1H), 8.42 (d, 1H), 8.29 (d, 1H),8.17 (t, 1H), 7.95 (dt, 1H), 7.88 (d, 1H), 7.82 (dt, 1H), 7.42 (s, 1H),7.26 (d, 1H), 3.71 (s, 2H), 3.19 (q, 2H), 2.32 (t, 2H). msES + (458.96,460.97) B

¹H NMR (DMSO-d₆, 400 MHz): δ 12.60 (bs, 1H), 8.42 (m, 2H), 8.29 (d, 1H),7.95 (dt, 1H), 7.87 (dd, 1H), 7.82 (dt, 1H), 7.43 (s, 1H), 7.26 (d, 1H),4.12 (q, 1H), 3.79 (m, 2H), 1.21 (m, 3H). msES + (458.96, 460.97) C

¹H NMR (DMSO-d₆, 400 MHz): δ 12.68 (bs, 1H), 8.42 (dd, 1H), 8.29 (m,2H), 7.95 (dt, 1H), 7.87 (dd, 1H), 7.82 (dt, 1H), 7.43 (s, 1H), 7.26 (d,1H), 4.08 (ddd, 1H), 3.87 (dd, 1H), 3.80 (dd, 1H), 2.01 (m, 1H), 0.82(m, 6H). msES + (486.97, 488.98) B

¹H NMR (DMSO-d₆, 400 MHz): δ 13.2 (bs, 1H), 8.46 (d, 1H), 8.31 (d, 1H),7.96 (t, 1H), 7.87 (m, 2H), 7.70 (s, 1H), 7.23 (d, 1H). msES + (423.89,425.88) A

¹H NMR (DMSO-d₆, 400 MHz): δ 9.24 (dd, 1H), 8.45 (dd, 1H), 8.31 (d, 1H),7.95 (m, 2H), 7.83 (t, 1H), 7.71 (s, 1H), 7.24 (dd, 1H), 4.16 (s, 2H),1.35 (d, 9H). msES + (537.10, 539.10) N/A

¹H NMR (DMSO-d₆, 400 MHz): δ 9.33 (dd, 1H), 8.47 (dd, 1H), 8.31 (d, 1H),7.96 (m, 2H), 7.84 (t, 1H), 7.72 (s, 1H), 7.24 (dd, 1H), 4.06 (ddd, 1H),1.27 (d, 9H), 1.25 (d, 3H). msES + (551.12, 552.12) N/A

¹H NMR (DMSO-d₆, 400 MHz): δ 9.18 (dd, 1H), 8.46 (dd, 1H), 8.31 (d, 1H),7.94 (m, 2H), 7.82 (t, 1H), 7.70 (s, 1H), 7.24 (dd, 1H), 3.86 (ddd, 1H),2.05 (m, 1H), 1.33 (d, 9H), 0.83 (m, 6H). msES + (579.15, 581.16) N/A

¹H NMR (DMSO-d₆, 400 MHz): δ 12.82 (bs, 1H), 9.32 (t, 1H), 8.46 (d, 1H),8.31 (d, 1H), 7.95 (m, 2H), 7.84 (t, 1H), 7.72 (s, 1H), 7.24 (d, 1H),3.72 (d, 1H). msES + (480.96, 482.96) N/A

¹H NMR (DMSO-d₆, 400 MHz): δ 12.79 (bs, 1H), 9.30 (t, 1H), 8.47 (dd,1H), 8.31 (d, 1H), 7.93 (m, 2H), 7.84 (t, 1H), 7.72 (s, 1H), 7.24 (dd,1H), 4.15 (ddd, 1H), 1.26 (d, 3H). msES + (495.06, 496.07) N/A

¹H NMR (DMSO-d₆, 400 MHz): δ 12.95 (bs, 1H), 9.24 (dd, 1H), 8.53 (dt,1H), 8.40 (dt, 1H), 8.01 (m, 2H), 7.79 (s, 1H), 7.30 (d, 1H), 4.03 (ddd,1H), 2.15 (m, 1H), 0.89 (m, 6H). msES + (523.09, 525.10) N/A

Example 104 In Vitro Metabolic Stability

In vitro metabolic stability is assessed in rat and human livermicrosomes (RLM/HLM). The incubation mixer contained the following: 1 uMtest compound, 1 mg/mL HLM/RLM, 100 mM potassium phosphate buffer at pH7.4, 1 mM NADPH and 5 mM MgCl₂. This mixture is preincubated for 3 minbefore the 30 minute incubation at 37° C. The reaction is initiated withthe addition of NADPH and terminated by the addition of equal volume ofacetonitrile with internal standard. Incubation samples without NADPHare used as control samples. After vortexing and centrifugation, thesupernatant is injected onto LC-MS/MS for quantitation.

2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid and2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidare examined according to this procedure.

III In Vivo Testing Example 105 PO Dosing in Rats

Compounds prepared as described in examples 1, 3, 7, 8, and 9 areadministered PO to Male Sprague-Dawley Rats (250 grams; 3 animals pertest group). The test compounds are dissolved in aqueous sodiumhydroxide solution (0.2N), brought up to volume with phosphate bufferedsaline to a concentration of 0.6 mg/mL, and PO administered to theanimals at a concentration of 3 mg/kg (5 mL/kg). Plasma samples areremoved at 0.25, 0.5, 1, 3, 6, 12 and 24 hr after initial dose andanalyzed for presence of compound and possible metabolite. Urine samplesare also collected and analyzed for parent compound and/or metabolite.

Note that in some instances,2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid(eg 1) is a possible in vivo metabolite of the compounds described inexamples 2-9.

The plasma profiles of compounds 3, 8 and 9 are shown in the tablebelow:

t½ Tmax Cmax Clast AUC (hr * ug/mL) F Eg Analyte (hr) (hr) (ug/mL)(ug/mL) t = 0_6 t = _12 t = 12_24 t = 0_24 (%) Eg 3 Eg 1 875 10 0.1540.0681 0.180 (8%)  0.696 (32%)  1.33 (60%) 2.21 29 Eg 3 3.49 0.8330.0566 0.000518 0.145 (58%) 0.0798 (32%)  0.0256 (10%) 0.251 Eg 8 Eg 112 0.0965 0.0253 0.174 (12%) 0.505 (36%)  0.731 (52%) 1.41 19 Eg 8 2.991 0.110 0.000371 0.339 (69%) 0.0839 (17%)  0.0652 (13%) 0.488 Eg 9 Eg 112 0.0716 0.0160 0.0873 (9%)  0.323 (35%)  0.526 (56%) 0.936 13 Eg 92.69 2.67 0.0258 0.00469 0.0915 (49%)  0.0677 (36%)  0.0282 (15%) 0.187

The urinary excretion profile of compounds 1, 3, 7, 8 and 9 are shown inthe table below:

Total Urinary Urinary Distribution BA Excretion (%) Eg Analyte (%) % ofdose 0-6 h 6-12 h 12-24 h Eg 1 Eg 1 30 4.2  85*  11*  4* Eg 3 Eg 3 nd 774 20 7 Eg 1 nd 12 15 38 47  Eg 7 Eg 7 nd 26 63 30 7 Eg 1 nd 1 43 40 18 Eg 8 Eg 8 nd 8 63 32 5 Eg 1 nd 10  8 46 47  Eg 9 Eg 9 nd 1 66 26 9 Eg 1nd 9  8 41 52  *Plasma Distribution

FIG. 1 shows a graph of mean plasma concentration of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidat various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post dosing,as released by in vivo metabolism of compounds 3, 8 and 9, after POdosing to male rats (3 mg/kg).

FIG. 2 shows a graph of mean plasma concentrations of example 3 andexample 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

FIG. 3 shows a graph of mean plasma concentrations of example 8 andexample 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

FIG. 4 shows a graph of mean plasma concentrations of example 9 andexample 1(2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)aceticacid), at various time points (0.25, 0.5, 1, 3, 6, 12 and 24 hr) post POdosing to male rats (3 mg/kg).

Example 106 In Vivo Uric Acid Lowering Activity

The uric acid lowering activity of the compounds described herein isdetermined in a multiple ascending dose, double-blind,placebo-controlled study in healthy adult male human volunteers, asfollows.

The study is performed in compliance with the current version of thedeclaration of Helsinki and with the ICH note for guidance on goodclinical practice (CPMP/ICH/135/95).

16 healthy male individuals, aged 18-45 years inclusive, with a bodymass index (BMI) within 18-30 kg/m² inclusive, having provided a writteninformed consent, non smokers for at least 6 months, not using any drugtreatment for 2 weeks before screening (2 months for enzyme-inducingdrugs) except occasional Acetaminophen. The individuals are confined atthe clinical site beginning the day before dose administration until 72hours after the final dose administration on Day 17 and returned for afollow-up visit on Day 21±1.

The study is performed using2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid, potassium salt or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid,potassium salt, supplied as 100-mg solid powder in size 2 gelatincapsules. Matching placebo capsules are supplied as size 2 gelatincapsules. Individuals are randomized to receive the same number ofplacebo capsules as administered to the active individuals.

Capsules (active or placebo) are administered orally with 240 mL water30 min after a standard breakfast (morning dose) and dinner (eveningdose) for 14 days.

16 individuals (8 individuals [6 active and 2 placebo] per dose group).

a. Group 1: Placebo b. Group 2: 300 mg (3 × 100-mg capsules) example 1b.i.d. c. Group 3: 500 mg (5 × 100-mg capsules) example 1 b.i.d.

Blood is collected from the individuals on days 0, 3, 7, 14 and atfollow-up. Serum uric levels wearere measured using standard automatedprocedures.

Example 107 Human Clinical Trial Comparing Efficacy of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidversus Indomethacin

Design

This is a double-blind, parallel-group, multicenter, randomized, 5-daystudy.

Endpoints

The primary efficacy endpoint is:

-   a. Individual assessment of pain.

The secondary efficacy endpoints are:

-   a. Tenderness of the study joint;-   b. Swelling of the study joint; and-   c. Proportion of individuals discontinuation due to lack of    efficacy.    Treatment Regime

Individuals are randomized into two groups: a control group (n=100) andan experimental group (n=100).

The control group is administered Indomethacin (75 mg) sustained releasecapsule (2 times daily) for a total of two weeks.

The experimental group is administered2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid, potassium salt or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid,potassium salt supplied as 100-mg solid powder in size 2 gelatincapsules for a total of two weeks.

Inclusion Criteria

Male or Female

≧18 years of old

Diagnosed with gout according to the 1980 ARA Criteria for theClassification of Acute Arthritis of Primary Gout.

Experiencing an acute attack of clinically diagnosed gout <48 hoursprior to randomization.

Score a sum of 5 across the 3 symptom questions for pain (0- to 4-Likertscale), tenderness (0- to 3-point scales), and swelling [0- to 3-pointscales] with the pain score being at least moderate (i.e. 2, 3, or 4 onthe 0- to 4-Likert scale).

Female individuals of childbearing potential must have a negativepregnancy test.

Female individuals of childbearing potential must be infertile or oncontraception.

Stastical Methodology

The primary analysis is based on change from baseline in individualassessment of pain computed from the average of responses on Study Days2 through 5 using an intention-to-treat approach. All individualefficacy variables (except endpoints defined as proportions) areassessed by ANCOVA (model to include terms for study site, stratum[monoarticular versus polyarticular acute gout], baseline covariate, andtreatment group), pending no 2-factor interactions with treatment. Thecomparability of treatment groups is assessed by 95% confidenceintervals for pairwise treatment difference. The 95% confidence intervalfor individual assessment of pain must fall entirely within thecomparability bounds (i.e., ±0.5 Likert units). Endpoints defined asproportions are compared between groups using Fisher's exact test.Assumptions of normality and homogeneity are assessed by theShapiro-Wilk statistic and Levene's test, respectively. If a significantinteraction (pδ0.050) is found, then the nature of the interaction isassessed and further exploratory analyses is performed.

Example 108 Human Clinical Trial Comparing Efficacy of42-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidin Individuals Treated for Hypertension

Hypothesis

Thiazide-induced hyperuricemia decreases the efficacy of thiazides incontrolling BP, leads to endothelial dysfunction, and increases theincidence of insulin resistance and impaired glucose tolerance.

Study Design

This study is a randomized, double-blind, placebo-controlled clinicaltrial of 8-week duration in which a total of 220 African Americanindividuals with untreated stage I hypertension will be enrolled,randomized, and treated as follows:

The experimental group receives chlorthalidone (25 mg/day) and potassiumchloride (40 mEq/day) for 4 weeks. They are then randomized to add-on acompound of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid, potassium salt, or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid,potassium salt (300 mg/day) or placebo.

The dosage of2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidwill be adjusted to achieve serum uric acid levels between 4 and 5.5mg/dL. All individuals will receive a low-sodium diet.

Endpoints

The primary endpoint is reduction in systolic BP.

The secondary endpoints measure changes in endothelial function,ambulatory blood pressure, body composition, systemic inflammation,metabolic parameters, oxidant stress, and renal hemodynamics.

Inclusion Criteria:

African American (including black individuals born in the Caribbean,Africa, Canada, etc.)

Male or Female

18 years of age or older

Untreated with any antihypertensive agent, with an average sittingclinic BP of between 140/90 and 159/99 mm Hg

Random spot urine protein/creatinine ratio of less than 0.5(approximates a 24-hour urinary protein excretion of 500 mg/day)

Calculated MDRD GFR of greater than or equal to 60 ml/min/1.73/m^2

No allopurinol or probenecid intake for at least one month prior tostudy entry

Exclusion Criteria

-   History of cancer or accelerated hypertension-   Confirmed total white cell count of less than 2,500/mm^3, anemia, or    thrombocytopenia-   Known history of liver disease-   Known secondary cause of hypertension-   Known presence of diabetes or fasting blood glucose greater than or    equal to 126 mg/dL-   History of heart failure, acute myocardial infarction, or stroke or    on a β-blocker or calcium channel blocker for cardiovascular    indications other than for lowering blood pressure-   Abnormal EKG requiring medical intervention-   History of clinical or renal biopsy or evidence of renal parenchymal    disease-   Acute gout attack within 2 weeks of study entry-   History of drug abuse in the last 2 years, including narcotics,    cocaine, or alcohol (greater than 21 drinks/week)-   Arm circumference of greater than 52 cm, which precludes measurement    with a ‘thigh’ BP cuff-   Pregnant or planning to become pregnant during the study, or    breastfeeding-   History of noncompliance, are unable to comply with the study    requirements, or who are currently participating in another study-   Not fasting prior to obtaining screening laboratory data. If a    participant has clearly not fasted, we will exclude those    individuals with casual blood glucose levels of greater than or    equal to 200 mg/dL. In the event that a fasting blood sugar exceeds    126 mg/dL, it will be reconfirmed on a blood glucose measurement    obtained on a subsequent day, per American Diabetes Association    criteria.

Example 109 Human Clinical Trial for Hyperuricemia or Hyperuricosuria

Study Design

This study is a randomized, double-blind, placebo-controlled clinicaltrial of 4-week duration in which a total of 100 individuals withatherosclerosis will be enrolled, randomized, and treated as follows:

The experimental group receives2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid, potassium salt, or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid,potassium salt (300 mg/day). The control group will receive atorvastatin(80-mg daily).

Main Criteria for Inclusion

-   Male and female individuals-   Between 30-75 years of age-   At least one obstruction in a major cardiac vessel with at least a    20% luminal diameter narrowing by visual estimation.-   A “target vessel” for IVUS interrogation with no more than 50%    luminal narrowing throughout a segment that was a minimum of 30 mm    in length (the “target segment”). The target vessel must not have    undergone previous intervention, nor have been a candidate for    intervention at the time of Baseline catheterization.-   Low-density lipoprotein cholesterol (LDL-C) between 125 and 210    mg/dL following a 4- to 10-week washout period if the individual is    taking antihyperlipidemic medication.-   Uric acid levels in the blood exceed 360 μmol/L (6 mg/dL) for a    female individual or 400 μmol/L (6.8 mg/dL) for a male individual;    or uric acid levels in urine exceed 800 mg/day (in a male    individual) and greater than 750 mg/day (in a female individual).    Endpoints

The primary efficacy parameter is restoration of uric acid levels tomedically-acceptable levels.

The secondary endpoints are:

-   a. Change in TPV-   b. Change in percent plaque PPV

Example 110

2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroaceticacid or2-(5-Bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acidis administered to 12 healthy subjects as follows:

-   a. 100 mg, fasted state (4 subjects)-   b. 100 mg, fed state (4 subjects)-   c. 200 mg, fasted state (4 subjects)

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested toindividuals skilled in the art are to be included within the spirit andpurview of this application and scope of the appended claims.

1. A compound of formula (II), or a pharmaceutically acceptable salt,ester or tautomer thereof:

wherein: W is O, S, S(O), S(O)₂, NH, N(optionally substituted alkyl),CH₂, CH₂O, CH₂S or CH₂NH; R¹ is F, Cl, Br, I, CH₂F, CF₂H, CF₃, CN, OH,NO₂, NH₂, NH(alkyl) or N(alkyl)(alkyl), SO₂CH₃, SO₂NH₂, SO₂NHCH₃,CO₂-alkyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkoxy, optionally substituted S-alkyl,optionally substituted cycloalkyl, or optionally substitutedheterocycle, a is 0, 1 or 2; R^(a) is H or optionally substituted C₁₋₃alkyl; R^(a′) is H or optionally substituted C₁₋₃ alkyl; or R^(a) andR^(a′) together with the carbon atom to which they are attached form anoptionally substituted, 3-, 4-, 5- or 6-membered ring, optionallycomprising 1 or 2 heteroatoms selected from O, N and S; R^(b), R^(c),R^(e) and R^(f) are each independently H, F, Cl, Br, I, CF₃, CN, alkyl,cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl; R^(d) is F, Cl,Br, I, CF₃, CN, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO₂H, COOR′,CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂, S(O)₂NHR′, S(O)₂NR′R″,aryl, heterocyclyl or heteroaryl; wherein R′ is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; R″ is methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or R′and R″ together with the nitrogen atom to which they are attached forman optionally substituted, saturated or unsaturated 4-, 5- or 6-memberedheterocyclic ring; or R^(b) and R^(c), or R^(c) and R^(d), or R^(d) andR^(e), or R^(e) and R^(f) together with the two carbon atoms to whichthey are attached, form an optionally substituted, aromatic ornon-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2heteroatoms selected from O, N and S, and wherein said ring may beoptionally fused to 1 or 2 additional optionally substituted, aromaticor non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or2 heteroatoms selected from O, N and S; and wherein the optionalsubstituents are each independently F, Cl, Br, I, CF₃, CN, alkyl,cycloalkyl, cyclopropylmethyl, NH₂, NHR′, NR′R″, OH, OR′, SH, SR′,C(O)R′, CO₂H, COOR′, CONH₂, CONHR′, CONR′R″, SO₃H, S(O)₂R′, S(O)₂NH₂,S(O)₂NHR′, S(O)₂NR′R″, aryl, heterocyclyl or heteroaryl; x is 0 or 1; yis 0 or 1; z is 0 or 1; R^(x), R^(x′), R^(y), R^(y′), R^(z) and R^(z′)are each independently H, F, Cl, Br, or optionally substituted C₁₋₃alkyl; or R^(x) and R^(x′), or R^(y) and R^(y′), or R^(z) and R^(z′), orR^(x) and R^(y), or R^(y) and R^(z), or R^(x) and R^(z) together withthe carbon atoms to which they are attached, form an optionallysubstituted, aromatic or non-aromatic, 3-7 membered ring, optionallycomprising 1 or 2 heteroatoms selected from O, N and S, and wherein saidring may be optionally fused to 1 or 2 additional optionallysubstituted, aromatic or non-aromatic, 5-, 6- or 7-membered rings,optionally comprising 1 or 2 heteroatoms selected from O, N and S; A isH, C(O)O—B¹ or C(O)NH—B²; wherein B¹ is H, optionally substituted C₁₋₆alkyl or a pharmaceutically acceptable cation; B² is H or optionallysubstituted C₁₋₆ alkyl; and wherein all alkyl, alkylene, cycloalkyl,heterocyclyl, aryl and heteroaryl moieties may be optionally furthersubstituted.
 2. The compound of claim 1, wherein W is S.
 3. The compoundof claim 1, wherein R¹ is F, Cl, Br, CH₂F, CF₂H, CF₃, NH₂, or CH₃. 4.The compound of claim 1, wherein W is S; and R¹ is Br.
 5. The compoundof claim 1, wherein a is 1; R^(a) is H; and R^(a′) is H.
 6. The compoundof claim 1, wherein A is C(O)O—B¹.
 7. The compound of claim 1, wherein Ais C(O)O—B¹; x is 1; and R^(x) and R^(x′) are not H.
 8. The compound ofclaim 1, wherein R^(x) and R^(x′) together with the carbon atoms towhich they are attached, form an optionally substituted, non-aromatic 3membered ring.
 9. The compound of claim 1, wherein R^(b), R^(c), R^(e)and R^(f) are all H.
 10. The compound of claim 1, wherein R^(b) andR^(c) together with the two carbon atoms to which they are attached,form an aromatic, 6-membered ring.
 11. A method of treating gout in anindividual, the method comprising administering to the individual atherapeutically effective amount of a compound of claim
 1. 12. A methodof treating hyperuricemia in an individual or reducing serum uric acidin an individual in need thereof, the method comprising administering tothe individual a therapeutically effective amount of a compound ofclaim
 1. 13. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1, and a pharmaceuticallyacceptable excipient.